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  • Dupilumab as a potential steroid-sparing treatment for IgG4-related disease
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-14
    Emanuel Della-Torre; Marco Lanzillotta; Mona-Rita Yacoub

    We read with interest the article from Simpson et al on the efficacy of dupilumab—an anti-IL-4 receptor alfa monoclonal antibody—in a patient with multi-organ IgG4-related disease (IgG4-RD) involving the retroperitoneum and, apparently, the prostate and the parotid glands.1 According to the case presentation, the patient refused immunosuppressive agents due to the risk of adverse events, and treating physicians decided to start him on 40 mg oral prednisone. Subcutaneous dupilumab was added based on multiple concomitant poorly controlled atopic manifestations including asthma, dermatitis and periorbital angioedema. Prednisone was tapered over 2 months and then withdrawn. Dupilumab was administered subcutaneously at initial dose of 600 mg, followed by 300 mg injections every other week for 12 months. Three months later, amelioration of all manifestations was observed, and after 12 months on dupilumab, retroperitoneal fibrosis was dramatically improved. Sensible decrease in …

    更新日期:2020-01-15
  • Response to: ‘Causal association of gut microbiome on the risk of rheumatoid arthritis: a Mendelian randomisation study’ by Lee
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-10
    Jun Inamo

    I am grateful to Dr Young Ho Lee1 for response to my article.2 Although my study demonstrated non-causal association between gut microbiome and the risk of rheumatoid arthritis (RA), the author demonstrated significant association between them. First, the reason why different conclusions were drawn from two studies is that I extracted only ‘Gut microbiota (bacterial taxa) (unit decrease)’ from variables of exposures in harmonised dataset before conducting Mendelian randomisation (MR) (R script is …

    更新日期:2020-01-10
  • Causal association of gut microbiome on the risk of rheumatoid arthritis: a Mendelian randomisation study
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-10
    Young Ho Lee

    I read with interest the articles by Inamo1 and Alpizar-Rodriguez et al 2 regarding the effects of the gut microbiome on the risk of rheumatoid arthritis (RA). The Mendelian randomisation (MR) study suggested that dysbiosis may be a secondary phenomenon, rather than a trigger, in the pathogenesis of RA,1 while the cohort study by Alpizar-Rodriguez et al suggested a role for intestinal dysbiosis in the development of RA.2 However, some methodological issues in the MR study must be discussed. First, I applied a …

    更新日期:2020-01-10
  • Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-10
    Tawnie J Braaten; Julie R Brahmer; Patrick M Forde; Dung Le; Evan J Lipson; Jarushka Naidoo; Megan Schollenberger; Lei Zheng; Clifton O Bingham 3rd; Ami A Shah; Laura C Cappelli

    Objective We sought to investigate the long-term outcomes of patients who develop immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA), to define factors associated with IA persistence after ICI cessation, the need for immunosuppressants and the impact of these medications on underlying malignancies. Methods We conducted a prospective observational study of patients referred for IA associated with ICIs. Patients were recruited from June 2015 to December 2018. Information was obtained at the baseline visit, and follow-up visits occurred at varying intervals for up to 24 months from ICI cessation. Kaplan-Meier curves were developed to characterise IA persistence. Cox proportional hazards models were used to assess the influence of various factors on IA persistence. Logistic regression was used to evaluate the impact of IA treatment on tumour response. Results Sixty patients were monitored with a median follow-up after ICI cessation of 9 months. A majority (53.3%) had active IA at their most recent follow-up. IA was less likely to improve in those with longer duration of ICI use, in those receiving combination ICI therapy, and in patients with multiple other immune-related adverse events. Tumour response did not appear to be impacted by immunosuppression. Although not statistically significant, persistent IA was correlated with a better tumour response (complete or partial response). Conclusion ICI-induced IA can become a long-term disease necessitating management by rheumatology for immunomodulatory treatment. Importantly, the use of immunomodulatory treatment has not been shown to impact cancer outcomes in this study.

    更新日期:2020-01-10
  • Dupilumab as a novel steroid-sparing treatment for IgG4-related disease
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-10
    Rachel S Simpson; Stephanie Ka Ching Lau; Jason Kihyuk Lee

    IgG4-related disease (IgG4-RD) is a rare fibroinflammatory, multisystemic condition with a relapsing-remitting progression.1 The level of serum IgG4 correlates with inflammatory activity and organ involvement.1 Glucocorticoids are first line for IgG4-RD, but there are numerous adverse effects with chronic use.2 Dupilumab is a monoclonal antibody that acts on the interleukin 4 (IL-4) receptor alpha, shared by the IL-4 and IL-13 receptors.1 IL-4 causes isotype switching from IgM to IgG4 and IL-13 is implicated in fibrosis.3 Thus, it was postulated by the authors to investigate dupilumab as a novel steroid-sparing treatment for IgG4-RD. A 67-year-old man with no known allergies and a history of sensory neural hearing loss, recurrent bronchitis, spinal stenosis, moderate positional obstructive sleep apnoea, asthma, atopic dermatitis (which caused swelling around his eyes) and allergic rhinoconjunctivitis underwent extensive investigations over the past 2 years due to suspected IgG4-RD. The patient’s initial complaint was pruritic erythematous lesions on the legs, arms, chest and palms. …

    更新日期:2020-01-10
  • Neuropsychiatric events in systemic lupus erythematosus: a longitudinal analysis of outcomes in an international inception cohort using a multistate model approach
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-08
    John G Hanly; Murray B Urowitz; Caroline Gordon; Sang-Cheol Bae; Juanita Romero-Diaz; Jorge Sanchez-Guerrero; Sasha Bernatsky; Ann E Clarke; Daniel J Wallace; David A Isenberg; Anisur Rahman; Joan T Merrill; Paul R Fortin; Dafna D Gladman; Ian N Bruce; Michelle Petri; Ellen M Ginzler; Mary Anne Dooley; Rosalind Ramsey-Goldman; Susan Manzi; Andreas Jönsen; Graciela S Alarcón; Ronald F van Vollenhoven; Cynthia Aranow; Meggan Mackay; Guillermo Ruiz-Irastorza; Sam Lim; Murat Inanc; Kenneth C Kalunian; Søren Jacobsen; Christine A Peschken; Diane L Kamen; Anca Askanase; Vernon Farewell

    Objectives Using a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus erythematosus (SLE) patients. Methods Annual assessments for 19 NP events attributed to SLE and non-SLE causes, physician determination of outcome and patient HRQoL (short-form (SF)-36 scores) were measured. Time-to-event analysis and multistate modelling examined the onset, recurrence and transition between NP states. Results NP events occurred in 955/1827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. In the first 2 years of follow-up the relative risk (95% CI) for SLE NP events was 6.16 (4.96, 7.66) and non-SLE events was 4.66 (4.01, 5.43) compared with thereafter. Patients without SLE NP events at initial assessment had a 74% probability of being event free at 10 years. For non-SLE NP events the estimate was 48%. The majority of NP events resolved over 10 years but mortality was higher in patients with NP events attributed to SLE (16%) versus patients with no NPSLE events (6%) while the rate was comparable in patients with non-SLE NP events (7%) compared with patients with no non-SLE events (6%). Patients with NP events had lower SF-36 summary scores compared with those without NP events and resolved NP states (p<0.001). Conclusions NP events occur most frequently around the diagnosis of SLE. Although the majority of events resolve they are associated with reduced HRQoL and excess mortality. Multistate modelling is well suited for the assessment of NP events in SLE.

    更新日期:2020-01-09
  • The earlier, the better or the worse? Towards accurate management of patients with arthralgia at risk for RA
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-08
    Annette van der Helm-van Mil; Robert B M Landewé

    The favourable long-term results of early treatment in patients with classified rheumatoid arthritis have resulted in an increasing interest in the diseases phases preceding clinical arthritis. The hypothesis to test is that an intervention in these early phases may better prevent or reduce disease persistence than an intervention when arthritis has become clinically manifest. While several placebo-controlled trials are still ongoing, to date there is no firm evidence that this hypothesis truly holds. Therefore, it is important to reflect on the current status of arthralgia preceding clinical arthritis. Inherent to every new field of research, attitudes are conflicting, with opinions propagating innovation (based on the fear of undertreatment) on the one hand, and critical sounds pleading for more restraint (fear of overtreatment) on the other hand. In this Viewpoint, we will examine these divergent opinions, relate them to a preferred ultimate scenario and provide considerations for future studies and daily practice.

    更新日期:2020-01-09
  • Enrichment of polyfunctional T cells in PsA synovial tissue. Response to: ‘Polyfunctional TEM cells in psoriatic arthritis synovium skewed towards Th17 cells’ by Raychaudhuri et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-08
    Mary Canavan; Sarah M Wade; Douglas J Veale; Ursula Fearon

    We read with interest the research letter by Raychaudhuri et al , which examines the frequencies of cytokine producing CD4+ memory T cells in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) synovial fluid mononuclear cells (SFMC) compared with peripheral blood mononuclear cells (PBMC).1 The authors examined the frequencies of single cytokine-producing T cells, specifically interleukin (IL)-17A+, IL-22+, tumour necrosis factor (TNF)+, interferon gamma (IFNγ)+ or IL-23R+ and report that Th17 cells are enriched in PsA SFMC, while RA is skewed to a Th1-like profile. In our previous publication, Wade et al ,2 we reported the frequencies of both single cytokine-producing and multiple cytokine (polyfunctional)-producing T cells, in addition to the frequencies of Th1, Th17 and exTh17 cells by using the Th17 lineage marker CD161. In our study, however, we reported these findings in synovial tissue biopsies from PsA patients, as opposed to …

    更新日期:2020-01-09
  • 'Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation’ by Braaten et al: another point of view
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-06
    Fulvia Ceccarelli; Andrea Botticelli; Alain Jonathan Gelibter; Ilaria Leccese; Ramona Lucchetti; Enrico Cortesi; Guido Valesini; Paolo Marchetti; Fabrizio Conti

    We read with interest the study published by Braaten and colleagues, analysing the long-term outcomes of 60 patients developing persistent inflammatory arthritis (IA) after immune checkpoint inhibitors (ICIs) cessation. The most relevant result of the study was the presence of active arthritis in more than half of the patients at the last follow-up visit.1 We report here our experience in the context of a joint oncology/rheumatology outpatient clinic, in order to evaluate the risk of developing IA in patients treated by anti-PD1 drugs. During 1-year period, we consecutively assessed all the adult patients candidate to anti-PD1 treatment, referring to the Oncology Unit at the Sapienza University of Rome. After treatment starts, in the case of musculoskeletal manifestations, patients were referred to the Sapienza Arthritis Center, Rheumatology Unit, Sapienza University of Rome. Arthritis was defined as the occurrence of at least one episode of clinical synovitis, with morning stiffness lasting at least 30 min. …

    更新日期:2020-01-07
  • Chronic inflammatory arthritis following checkpoint inhibitor therapy for cancer: game changing implications
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-03
    Leonard Calabrese; Xavier Mariette

    The use of immune checkpoint inhibitor (ICI) therapy for cancer is now a pillar of oncological therapeutics and growing, with an estimated 43.5% of all tumours falling within current labelling indications for use.1 Eventually as the accessibility to ICI therapy increases, these data have staggering implications, given that an estimated number of new cancers in Europe and the USA exceeds 5 million individuals yearly.2 As a byproduct of this tidal wave of newly exposed patients to various forms of immunotherapy with estimates that 10%–20% or more who may develop serious immune related adverse events (irAEs),3 it is inevitable that the evaluation and care of such patients will pose a challenge to existing healthcare systems and likely create a space for a new specialty to manage such. From a rheumatological perspective, let us now consider that an estimated 3%–7% of ICI exposed patients may develop inflammatory arthritis (IA),4 5 making it seem inevitable that ICI associated IA will become ever more commonplace, giving us pause to ask ourselves what our current understanding of this disorder is and how prepared we are to manage it. These irAEs are heterogeneous and appear to differ in their presentations, similarity to existing constructs of autoimmune diseases and their natural history. To help focus the discussion regarding these complications and based on the available data on IrAEs, we propose a classification of them into three main categories (box 1). Most irAEs are self-limiting in nature and while they may have lasting clinical effects such as ongoing requirement for hormone replacement therapy in some endocrinopathies, the inflammatory phase of these illnesses is largely self-limiting with few exceptions, with less than 10% requiring additional therapy after suppression with glucocorticoids.6 A second category is the development of a classical autoimmune disease in subjects who were …

    更新日期:2020-01-04
  • Response to: ‘Frequency of MRI changes suggestive of axial spondyloarthritis in the axial in a large population-based cohort of individuals aged <45 years’ by Parperis
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-03
    Xenofon Baraliakos; Adrian Richter; Carsten O Schmidt; Juergen Braun

    We agree with the authors of the comment that caution in the interpretation of MRI is needed, though we think this is generally the case for any kind of imaging techniques. Regarding the axial skeleton including the spine and the sacroiliac joints (SIJs) this is particularly critical if identification of patients with axial spondyloarthritis (axSpA) is pursued. In this context our study1 confirms earlier data.2 We conclude that false positive MRI findings account for much of the confusion that has been created in relation to the Assessments in Spondyloarthritis International Society (ASAS) classification criteria.3 However, Dr Parperis has a different issue4 since he proposes …

    更新日期:2020-01-04
  • Novel ultrasonographic Halo Score for giant cell arteritis: assessment of diagnostic accuracy and association with ocular ischaemia
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-03
    Kornelis S M van der Geest; Frances Borg; Abdul Kayani; Davy Paap; Prisca Gondo; Wolfgang Schmidt; Raashid Ahmed Luqmani; Bhaskar Dasgupta

    Objectives Ultrasound of temporal and axillary arteries may reveal vessel wall inflammation in patients with giant cell arteritis (GCA). We developed a ultrasound scoring system to quantify the extent of vascular inflammation and investigated its diagnostic accuracy and association with clinical factors in GCA. Methods This is a prospective study including 89 patients suspected of having GCA, of whom 58 had a confirmed clinical diagnosis of GCA after 6 months follow-up. All patients underwent bilateral ultrasound examination of the three temporal artery (TA) segments and axillary arteries, prior to TA biopsy. The extent of vascular inflammation was quantified by (1) counting the number of TA segments and axillary arteries with a halo and (2) calculating a composite Halo Score that also incorporated the thickness of each halo. Results Halo counts and Halo Scores showed moderate diagnostic accuracy for a clinical diagnosis of GCA. They correlated positively with systemic inflammation. When compared with the halo count, the Halo Score correlated better with C-reactive protein (CRP) levels and allowed to firmly establish the diagnosis of GCA in more patients. Higher halo counts and Halo Scores were associated with a higher risk of ocular ischaemia. They allowed to identify subgroups of patients with low risk (≤5%) and high risk of ocular ischaemia (>30%). Conclusions Ultrasound halo scoring allows to quantify the extent of vascular inflammation in GCA. Extensive vascular inflammation on ultrasound may provide strong diagnostic confirmation and associates with ocular ischaemia in GCA.

    更新日期:2020-01-04
  • Efficacy of JAK 1/2 inhibition in the treatment of diffuse non-scarring alopecia due to systemic lupus erythematosus
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-03
    Keisuke Maeshima; Hirotaka Shibata

    The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is crucial for the autocrine loop of type I interferons (IFNs) and is located upstream of important systemic lupus erythematosus (SLE)-associated pathogenic proinflammatory cytokines and chemokines. Baricitinib is a JAK 1/2 inhibitor approved for treating rheumatoid arthritis and is also being tested in other diseases, including SLE. Baricitinib improved the proportion of patients with SLE who achieved arthritis or rash resolution; however, the subset of patients with skin involvement was not reported in the study.1 Alopecia is one of the most common cutaneous symptoms in SLE. Patients can exhibit different subtypes of alopecia.2 Diffuse non-scarring hair loss, which is the most frequently observed type of alopecia in patients with SLE, is not life-threatening, but substantially affects quality of life for cosmetic reasons and may reflect latent …

    更新日期:2020-01-04
  • Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-31
    Emmanuel Monnet; Ernest H Choy; Iain McInnes; Tamta Kobakhidze; Kathy de Graaf; Philippe Jacqmin; Geneviève Lapeyre; Cristina de Min

    Objectives Anti-citrullinated protein antibodies (ACPAs) form immune complexes with citrullinated proteins binding toll-like receptor (TLR) 4, which has been proposed as a mediator of rheumatoid arthritis (RA). NI-0101 is a first-in-class humanised monoclonal antibody blocking TLR4, as confirmed by inhibition of in vivo lipopolysaccharide-induced cytokine release in healthy volunteers. This study was design to confirm preclinical investigations supporting a biomarker-driven approach for treatment of patients with RA who present positive for these immune complexes. Methods Placebo-controlled, double-blind, randomised (2:1) trial of the tolerability and efficacy of NI-0101 (5 mg/kg, every 2 weeks for 12 weeks) versus placebo in ACPA-positive RA patients with inadequate response to methotrexate. Efficacy measures included Disease Activity Score (28-joint count) with C reactive protein (DAS28-CRP), European League Against Rheumatism (EULAR) good and moderate responses, and American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses. Subgroup analyses defined on biomarkers were conducted. Pharmacokinetics, pharmacodynamics and safety were reported. Results 90 patients were randomised (NI-0101 (61) and placebo (29)); 86 completed the study. No significant between-group difference was observed for any of the efficacy endpoints. Subgroup analyses using baseline parameters as covariants did not reveal any population responding to NI-0101. Treatment-emergent adverse events occurred in 51.7% of patients who received placebo versus 52.5% for NI-0101. Conclusions We demonstrate for the first time that in RA, a human immune-mediated inflammatory disease, blocking the TLR4 pathway alone does not improve disease parameters. Successful targeting of innate immune pathways in RA may require broader and/or earlier inhibitory approaches.

    更新日期:2019-12-31
  • Response to: ‘response to: irritable bowel syndrome symptoms in axial spondyloarthritis more common than among healthy controls: is it an overlooked comorbidity?’ by Proft et al.
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-31
    Johan Karlsson Wallman; Elisabeth Mogard; Jan Marsal; Kristofer Andréasson; Anna Jöud; Mats Geijer; Lars Erik Kristensen; Elisabet Lindqvist; Tor Olofsson

    We appreciate the correspondence by Proft et al regarding our study entitled ‘Irritable bowel syndrome symptoms in axial spondyloarthritis more common than among healthy controls: is it an overlooked comorbidity?’,1 2 and thank Annals of the Rheumatic Diseases for the opportunity to respond. We also acknowledge the major contributions of Proft et al to the field of spondyloarthritis (SpA) research. Regarding our main result, that irritable bowel syndrome (IBS) symptoms are significantly more common among patients with axial SpA without known inflammatory bowel disease (IBD) (n=182) than in healthy controls (n=50), Proft et al point out that the increased prevalence is likely due to other causes than actual clinical IBS (in particular gut inflammation and side effects of non-steroidal anti-inflammatory drug (NSAID) use). In response to this, we would first like to draw attention to the rule-out character of the ROME III criteria used to diagnose IBS, as also brought up by Proft et al . According to these, a clinical IBS diagnosis requires both a typical constellation of gastrointestinal symptoms, as defined by the criteria, and the exclusion of organic causes such as IBD or malignancies. The main finding of our study, that 30% of the axial SpA patients in the well-characterised SPARTAKUS cohort reported IBS symptoms, as opposed to 16% of healthy controls (sex/age-adjusted OR 2.5; p=0.036), refers to self-reported symptoms, as defined by the ROME III criteria, but irrespective of their underlying cause (and hence not per se meeting the exclusion condition). This important distinction—between IBS symptoms and a clinical IBS diagnosis—is made throughout our report. In the second part of our study, we then performed a hypothesis-generating analysis of potential drivers behind the observed IBS symptoms. Similar to Proft et al , …

    更新日期:2019-12-31
  • Do we need the PFAPA syndrome in adults with non-monogenic periodic fevers?
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-31
    Antoine Fayand; Veronique Hentgen; Stephanie Ducharme-Bénard; Pierre Quartier; Brigitte Bader-Meunier; Isabelle Koné-Paut; Gilles Grateau; Sophie Georgin-Lavialle

    We read with great interest the article by Gattorno et al proposing a new set of criteria for the classification of autoinflammatory recurrent fevers.1 This year’s Paediatric Rheumatology INternational Trials Organisation(PRINTO) criteria are the third set of criteria for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome in 3 years.1–3 While these three different sets share common points, they also include distinct clinical features, thus resulting in discrepancies in the classification of patients. To illustrate this issue, we report the clinical characteristics of a cohort of 34 consecutive adult patients (see table 1) followed in our centre between 2010 and 2018, and diagnosed with PFAPA based on the modified Marshall’s criteria4 (available as online supplementary material) with the exclusion of age at onset. …

    更新日期:2019-12-31
  • Correspondence on ‘Shared epitope defines distinct associations of cigarette smoking with levels of anticitrullinated protein antibody and rheumatoid factor’ by Ishikawa et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-31
    Cristina Regueiro; Antonio Gonzalez

    We read with great interest the paper of Ishikawa et al ,1 which addressed the link between smoking and the levels of anti-citrullinated protein antibodies(ACPA) and rheumatoid factor (RF) in a total of 6239 Japanese rheumatoid arthritis (RA) patients. We particularly appreciate the detailed smoking history collected that allowed a very detailed analysis. The authors collected information about the number of cigarette packs smoked per day, the years smoking and the time of smoke cessation when it was present. They also distinguished the ever smoker patients in three categories: smokers at disease onset, ex-smokers before onset and smokers after onset, which looks like a very …

    更新日期:2019-12-31
  • Single-cell RNA-seq analysis identifies meniscus progenitors and reveals the progression of meniscus degeneration
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-23
    Hao Sun; Xingzhao Wen; Hongyi Li; Peihui Wu; Minghui Gu; Xiaoyi Zhao; Ziji Zhang; Shu Hu; Guping Mao; Ruofan Ma; Weiming Liao; Zhiqi Zhang

    Objectives The heterogeneity of meniscus cells and the mechanism of meniscus degeneration is not well understood. Here, single-cell RNA sequencing (scRNA-seq) was used to identify various meniscus cell subsets and investigate the mechanism of meniscus degeneration. Methods scRNA-seq was used to identify cell subsets and their gene signatures in healthy human and degenerated meniscus cells to determine their differentiation relationships and characterise the diversity within specific cell types. Colony-forming, multi-differentiation assays and a mice meniscus injury model were used to identify meniscus progenitor cells. We investigated the role of degenerated meniscus progenitor (DegP) cell clusters during meniscus degeneration using computational analysis and experimental verification. Results We identified seven clusters in healthy human meniscus, including five empirically defined populations and two novel populations. Pseudotime analysis showed endothelial cells and fibrochondrocyte progenitors (FCP) existed at the pseudospace trajectory start. Melanoma cell adhesion molecule ((MCAM)/CD146) was highly expressed in two clusters. CD146+ meniscus cells differentiated into osteoblasts and adipocytes and formed colonies. We identified changes in the proportions of degenerated meniscus cell clusters and found a cluster specific to degenerative meniscus with progenitor cell characteristics. The reconstruction of four progenitor cell clusters indicated that FCP differentiation into DegP was an aberrant process. Interleukin 1β stimulation in healthy human meniscus cells increased CD318+ cells, while TGFβ1 attenuated the increase in CD318+ cells in degenerated meniscus cells. Conclusions The identification of meniscus progenitor cells provided new insights into cell-based meniscus tissue engineering, demonstrating a novel mechanism of meniscus degeneration, which contributes to the development of a novel therapeutic strategy.

    更新日期:2019-12-23
  • Germline genetic patterns underlying across familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome highlight T cell-initiated autoimmunity
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-23
    Yukai Wang; Shaoqi Chen; Jingyao Chen; Xuezhen Xie; Sini Gao; Chengpeng Zhang; Songxia Zhou; Jing Wang; Ruiqin Mai; Qisheng Lin; Jianqun Lin; Marco Matucci-Cerinic; Guohong Zhang; Daniel E Furst

    Objectives Familial aggregation of primary Sjögren’s syndrome (pSS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and co-aggregation of these autoimmune diseases (ADs) (also called familial autoimmunity) is well recognised. However, the genetic predisposition variants that explain this clustering remains poorly defined. Methods We used whole-exome sequencing on 31 families (9 pSS, 11 SLE, 6 RA and 5 mixed autoimmunity), followed by heterozygous filtering and cosegregation analysis of a family-focused approach to document rare variants predicted to be pathogenic by in silico analysis. Potential importance in immune-related processes, gene ontology, pathway enrichment and overlap analyses were performed to prioritise gene sets. Results A range from 1 to 50 rare possible pathogenic variants, including 39 variants in immune-related genes across SLE, RA and pSS families, were identified. Among this gene set, regulation of T cell activation (p=4.06×10−7) and T cell receptor (TCR) signalling pathway (p=1.73×10−6) were particularly concentrated, including PTPRC ( CD45 ), LCK , LAT–SLP76 complex genes ( THEMIS , LAT , ITK , TEC , TESPA1 , PLCL1) , DGKD , PRKD1 , PAK2 and NFAT5 , shared across 14 SLE, RA and pSS families. TCR-interactive genes P2RX7 , LAG3 , PTPN3 and LAX1 were also detected. Overlap analysis demonstrated that the antiviral immunity gene DUS2 variant cosegregated with SLE, RA and pSS phenotypes in an extended family, that variants in the TCR-pathway genes CD45 , LCK and PRKD1 occurred independently in three mixed autoimmunity families, and that variants in CD36 and VWA8 occurred in both RA-pSS and SLE-pSS families. Conclusions Our preliminary results define common genetic characteristics linked to familial pSS, SLE and RA and highlight rare genetic variations in TCR signalling pathway genes which might provide innovative molecular targets for therapeutic interventions for those three ADs.

    更新日期:2019-12-23
  • IFN-α kinoid in systemic lupus erythematosus: results from a phase IIb, randomised, placebo-controlled study
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-23
    Frederic A Houssiau; Aikaterini Thanou; Minodora Mazur; Edgar Ramiterre; Danny Alexis Gomez Mora; Maria Misterska-Skora; Risto Alfredo Perich-Campos; Svetlana A Smakotina; Sergio Cerpa Cruz; Bassem Louzir; Thérèse Croughs; Michael Lucas Tee

    Objective To evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care. Methods Patients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering. Results IFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN-K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable. Conclusions IFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering. Trial registration number [NCT02665364][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02665364&atom=%2Fannrheumdis%2Fearly%2F2019%2F12%2F22%2Fannrheumdis-2019-216379.atom

    更新日期:2019-12-23
  • Response to: ‘Development and initial validation of diagnostic gene signatures for systemic lupus erythematosus’ by Wang et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-20
    Martin Aringer; Karen Costenbader; Thomas Dörner; Sindhu R Johnson

    In their letter, Dr Wang and colleagues1 correctly remark that no novel molecular biomarkers were included in the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2019 classification criteria for systemic lupus erythematosus (SLE), although a variety of such markers were considered in the process, including the type I interferon signature.2 3 As cited by Wang et al …

    更新日期:2019-12-21
  • Polyfunctional TEM cells in psoriatic arthritis synovium skewed towards Th17 cells
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-20
    Smriti K Raychaudhuri; Christine Abria; Siba P Raychaudhuri

    We read the article by Wade et al 1 with great interest. With very elegant experiments, they have reported enrichment of polyfunctional T-lymphocytes in the synovial tissue of psoriatic arthritis (PsA); they have also noticed that polyfunctional synovial T-cells were positively associated with Disease Activity Index for Psoriatic Arthritis. We agree there are only limited studies in human autoimmune diseases which have addressed regulatory role of T-cell polyfunctionality of the activated effector memory T cells (TEM) in single cell suspensions. We have been working on TEM cell subpopulations in PsA and over years have demonstrated Th17, Th9 and mucosal-associated invariant T cells in PsA,2–4 which are also polyfunctional. In respect to studying polyfunctional T cells in PsA instead of focusing on Th1, Th17 and exTh17 cells,1 we took a different approach to look into the cytokine profile and polyclonality of these TEM cells in respect their profound role in the disease process of PsA such as (IL-17, IL-23R, IL-22 and TNFα) and also compared with that polyfunctional T cells of rheumatoid arthritis (RA) to see whether a role of polyfunctional T cells can be reproduced in an another autoimmune arthritis and if so to identify the differences in …

    更新日期:2019-12-21
  • Response to: ‘New 2019 SLE EULAR/ACR classification criteria are valid for identifying patients with SLE among patients admitted for pericardial effusion’ by Sacre et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-20
    Martin Aringer; Karen Costenbader; Thomas Dörner; Sindhu R Johnson

    In their letter, Dr Sacre and colleagues1 describe an interesting retrospective study on 129 patients with pericardial effusion, of whom 17 were diagnosed with systemic lupus erythematosus (SLE). The authors arrive at a reassuring sensitivity of 100% for the new European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2019 classification criteria.2 3 However, specificity was clearly lower at 84%, below the specificity of the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) criteria. The latter is a somewhat unexpected result. Based on the …

    更新日期:2019-12-21
  • Not only synovitis but also tenosynovitis needs to be considered: why it is time to update textbook images of rheumatoid arthritis
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-19
    Cleo Rogier; Silvia Hayer; Annette van der Helm-van Mil

    Rheumatoid arthritis (RA) is typically represented as synovitis and bone erosions of small joints. This classic picture resulted from comparing patients with RA with other rheumatic joint diseases for clinical and radiographic characteristics. Although different classification criteria for RA have been developed over time, this classic picture has not changed since the mid-20th century. During the last decennium, advanced imaging modalities, such as MRI and musculoskeletal ultrasound (US), have refined our understanding of tissues involved in RA. We will argue that tenosynovitis at the level of the hand and feet joints is a feature that deserves to be added as the third classic trait of RA. A feature can be considered as a disease trait when it occurs frequently and is specific, and when a new trait is considered its connection with the disease is not a substitute of an already acknowledged classic feature. We will study the occurrence of tenosynovitis in RA in the light of these principles. Many, but not all, tendons at the hand and feet joints are surrounded by a sheath.1 2 Tendon sheaths have a cell composition …

    更新日期:2019-12-20
  • Withdrawal of low-dose prednisone in SLE patients with a clinically quiescent disease for more than 1 year: a randomised clinical trial
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-18
    Alexis Mathian; Micheline Pha; Julien Haroche; Fleur Cohen-Aubart; Miguel Hié; Marc Pineton de Chambrun; Thi Huong Du Boutin; Makoto Miyara; Guy Gorochov; Hans Yssel; Patrick Cherin; Hervé Devilliers; Zahir Amoura

    Objectives To compare the efficacy to prevent flares of maintenance versus withdrawal of 5 mg/day prednisone in systemic lupus erythematosus (SLE) patients with clinically quiescent disease. Methods A monocentric, 12-month, superiority, open-label, randomised (1:1) controlled trial was conducted with 61 patients continuing 5 mg/day prednisone and 63 stopping it. Eligibility criteria were SLE patients who, during the year preceding the inclusion, had a clinically inactive disease and a stable SLE treatment including 5 mg/day prednisone. The primary endpoint was the proportion of patient experiencing a flare defined with the SELENA-SLEDAI flare index (SFI) at 52 weeks. Secondary endpoints included time to flare, flare severity according to SFI and British Isles Lupus Assessment Group (BILAG) index and increase in the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI). Results Proportion of patients experiencing a flare was significantly lower in the maintenance group as compared with the withdrawal group (4 patients vs 17; RR 0.2 (95% CI 0.1 to 0.7), p=0.003). Maintenance of 5 mg prednisone was superior with respect to time to first flare (HR 0.2; 95% CI 0.1 to 0.6, p=0.002), occurrence of mild/moderate flares using the SFI (3 patients vs 12; RR 0.2 (95% CI 0.1 to 0.8), p=0.012) and occurrence of moderate/severe flares using the BILAG index (1 patient vs 8; RR 0.1 (95% CI 0.1 to 0.9), p=0.013). SDI increase and adverse events were similar in the two treatment groups. Subgroup analyses of the primary endpoint by predefined baseline characteristics did not show evidence of a different clinical response. Conclusion Maintenance of long term 5 mg prednisone in SLE patients with inactive disease prevents relapse. Trial registration number [NCT02558517][1]; Results [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02558517&atom=%2Fannrheumdis%2Fearly%2F2019%2F12%2F18%2Fannrheumdis-2019-216303.atom

    更新日期:2019-12-19
  • Paradox of circulating TRMs. Response to: ‘Gut-derived CD8+ tissue-resident memory T cells are expanded in the peripheral blood and synovia of SpA patients’ by Guggino et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-18
    Zoya Qaiyum; Eric Gracey; YuChen Yao; Robert D Inman

    We were pleased to receive the correspondence of Guggino et al 1 commenting on our recent publication.2 Their studies confirm our findings of an expansion of cells with an expression profile consistent with tissue-resident memory cells (TRMs) in synovial fluid of spondyloarthritis (SpA). They have added the valuable insight that these cells are also expanded in gut tissues of patients with SpA. The CD8+ T cell in question reported by …

    更新日期:2019-12-19
  • LRBA deficiency: a new genetic cause of monogenic lupus
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-18
    Bernadete L Liphaus; Iris Caramalho; Andreia Rangel-Santos; Clóvis A Silva; Jocelyne Demengeot; Magda Maria Salles Carneiro-Sampaio

    Juvenile systemic lupus erythematosus (JSLE) is considered a polygenic disease, although identified causes of monogenic SLE and lupus-like syndrome are enlarging.1 2 The genetic basis of polyautoimmune syndromes is also being elucidated, now including lipopolysaccharide-responsive beige-like anchor (LRBA) deficiencies.3 We report a patient carrying a new deleterious LRBA mutation that associates with JSLE . The patient, a girl born from healthy consanguineous parents, presented recurrent respiratory infections since 1 year of age, and since 7 years of age, chronic non-bloody diarrhoea diagnosed as non-specific colitis, IgA deficiency (<1.0 mg/dL) and arthralgia. At 10 years of age, laboratory tests revealed normal C1q, C2, C3, C4, CH50 and lymphocyte counts, homogeneous antinuclear antibody (ANA; HEp-2 1/640) and negative anti-dsDNA. Six months later, she presented respiratory distress, acute diarrhoea, pericardial effusion, serum glucose of 724 mg/dL, positive anti-IAA (42 IU/mL), and type 1 diabetes (T1D) was diagnosed. When 11 years of age, she clearly fulfilled the American College of Rheumatology 1997 SLE classification criteria by presenting polyarthritis, pericarditis, autoimmune haemolytic anaemia, alopecia, persistent malar rash, homogeneous ANA (1/1280), positive anti-dsDNA (119 IU/mL, ELISA, confirmed by Crithidia luciliae ), anticardiolipin IgG, anti-thyroglobulin and anti-thyroid peroxidase. Prednisone and …

    更新日期:2019-12-19
  • Response to: ‘Clarification regarding the statement of the association between the recombinant zoster vaccine (RZV) and gout flares’ by Didierlaurent et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-18
    Chio Yokose; Hyon Choi

    We read with great interest the correspondence from Didierlaurent et al 1 regarding our recent report on the association between vaccination and risk of gout flares using a case-crossover design.2 In particular, we appreciate the clarification that the authors provided regarding the unsolicited adverse events reported during the 30 days after each vaccination, including episodes of gout, with incident gout cases surpassing reports of recurrent gout flares. While this is a notable difference from our online case-crossover study which included only patients with known gout and assessed for recurrent gout flares, this …

    更新日期:2019-12-19
  • Interleukin 1 receptor antagonist (IL1RN) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-18
    Mukundan Attur; Hua Zhou; Johathan Samuels; Svetlana Krasnokutsky; Michelle Yau; Jose U Scher; Michael Doherty; Anthony G Wilson; Jenny Bencardino; Marc Hochberg; Joanne M Jordan; Braxton Mitchell; Virginia B Kraus; Steven B Abramson

    Objective In these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA). Methods Over 1000 subjects who met American College of Rheumatology criteria for tibiofemoral OA were selected from three independent, National Institute of Health (NIH)-funded cohorts. CTA and TTG haplotypes formed from three SNPs of the IL1RN gene (rs419598, rs315952, rs9005) were assessed for association with radiographic severity, and risk for incident radiographic OA (rOA) in a nested case–control cohort. These IL1RN haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA. Results Carriage of the IL1RN TTG haplotype was associated with increased odds of more severe rOA compared with age-matched, sex-matched and body mass index-matched individuals. Examination of the osteoarthritis initiative Incidence Subcohort demonstrated that carriage of the TTG haplotype was associated with 4.1-fold (p=0.001) increased odds of incident rOA. Plasma IL-1Ra levels were lower in TTG carriers, while chondrocytes from TTG carriers exhibited decreased secretion of IL-1Ra. In patients with RA, the TTG haplotype was associated with increased DAS28, decreased plasma IL-1Ra and elevations of plasma inflammatory markers (hsCRP, interleukin 6 (IL-6)). Conclusion Carriage of the IL1RN TTG haplotype is associated with more severe rOA, increased risk for incident OA, and increased evidence of inflammation in RA. These data suggest that the IL1RN TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous ‘anti-inflammatory’ mechanisms.

    更新日期:2019-12-19
  • Response to: ‘Irritable bowel syndrome symptoms in axial spondyloarthritis more common than among healthy controls: is it an overlooked comorbidity?’ by Wallman et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-18
    Fabian Proft; Mikhail Protopopov; Valeria Rios Rodriguez; Murat Torgutalp; Britta Siegmund; Denis Poddubnyy

    We read with interest the letter by Wallman et al , that reported the prevalence of irritable bowel syndrome (IBS) in patients with axial spondyloarthritis (axial SpA).1 The authors present data from the population based SPondylARtrit TvÄrsnittsKohort Universitetssjukhuset i Skåne (SPARTAKUS) study,2 showing that symptoms meeting IBS criteria were significantly more frequent among patients with axial SpA without known inflammatory bowel diseases (IBD) (30%), than in controls (16%; OR: 2.5 (95% CI 1.1 to 5.7)). Authors conclude that IBS may be an overlooked frequent comorbidity of axial SpA warranting further research and increased awareness. In our view, this suggested high prevalence of IBS in patients with axial SpA might be …

    更新日期:2019-12-19
  • Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2019-12-17
    Maria Grigoriou; Aggelos Banos; Anastasia Filia; Pavlos Pavlidis; Stavroula Giannouli; Vassiliki Karali; Dionysis Nikolopoulos; Antigone Pieta; George Bertsias; Panayotis Verginis; Ioannis Mitroulis; Dimitrios T Boumpas

    Objectives Haematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs. Methods A global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence. Results Transcriptomic analysis of Lin−Sca-1+c-Kit+ haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)—but not of common lymphoid progenitors—reminiscent of a ‘trained immunity’ signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such as Cebpe , Cebpd and Csf3r , and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34+) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data. Conclusions Aberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare. Trial registration number 4948/19-07-2016.

    更新日期:2019-12-18
  • Greetings from the editor 2020
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Josef S Smolen

    A new decade of the 21st century is starting. We have experienced multiple shake-ups in the course of the last decade, the ‘teens-decade’—political ones and social ones, such as the climate crisis which affects us globally and might even influence the epidemiology of rheumatic diseases in the not too distant future. Hopefully the new decade will find solutions for some of the burning problems of the planet and its societies. In rheumatology, the first decade of this millennium brought novel therapies especially for rheumatoid arthritis (RA),1 2 changing the lives of millions of patients with RA around the world and making rheumatology one of the most successful medical specialties, attracting many young people to specialise in the field. The second decade brought several major therapeutic advances beyond tumour necrosis factor inhibitors especially for patients with psoriatic arthritis and axial spondyloarthritis3 4; the advent of biosimilars …

    更新日期:2019-12-17
  • EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Manuel Ramos-Casals; Pilar Brito-Zerón; Stefano Bombardieri; Hendrika Bootsma; Salvatore De Vita; Thomas Dörner; Benjamin A Fisher; Jacques-Eric Gottenberg; Gabriela Hernandez-Molina; Agnes Kocher; Belchin Kostov; Aike A. Kruize; Thomas Mandl; Wan-Fai Ng; Soledad Retamozo; Raphaèle Seror; Yehuda Shoenfeld; Antoni Sisó-Almirall; Athanasios G. Tzioufas; Claudio Vitali; Simon Bowman; Xavier Mariette

    The therapeutic management of Sjögren syndrome (SjS) has not changed substantially in recent decades: treatment decisions remain challenging in clinical practice, without a specific therapeutic target beyond the relief of symptoms as the most important goal. In view of this scenario, the European League Against Rheumatism (EULAR) promoted and supported an international collaborative study (EULAR SS Task Force) aimed at developing the first EULAR evidence and consensus-based recommendations for the management of patients with SjS with topical and systemic medications. The aim was to develop a rational therapeutic approach to SjS patients useful for healthcare professionals, physicians undergoing specialist training, medical students, the pharmaceutical industry and drug regulatory organisations following the 2014 EULAR standardised operating procedures. The Task Force (TF) included specialists in rheumatology, internal medicine, oral health, ophthalmology, gynaecology, dermatology and epidemiology, statisticians, general practitioners, nurses and patient representatives from 30 countries of the 5 continents. Evidence was collected from studies including primary SjS patients fulfilling the 2002/2016 criteria; when no evidence was available, evidence from studies including associated SjS or patients fulfilling previous sets of criteria was considered and extrapolated. The TF endorsed the presentation of general principles for the management of patients with SjS as three overarching, general consensus-based recommendations and 12 specific recommendations that form a logical sequence, starting with the management of the central triplet of symptoms (dryness, fatigue and pain) followed by the management of systemic disease. The recommendations address the use of topical oral (saliva substitutes) and ocular (artificial tear drops, topical non-steroidal anti-inflammatory drugs, topical corticosteroids, topical CyA, serum tear drops) therapies, oral muscarinic agonists (pilocarpine, cevimeline), hydroxychloroquine, oral glucocorticoids, synthetic immunosuppressive agents (cyclophosphamide, azathioprine, methotrexate, leflunomide and mycophenolate), and biological therapies (rituximab, abatacept and belimumab). For each recommendation, levels of evidence (mostly modest) and TF agreement (mostly very high) are provided. The 2019 EULAR recommendations are based on the evidence collected in the last 16 years in the management of primary 2002 SjS patients and on discussions between a large and broadly international TF. The recommendations synthesise current thinking on SjS treatment in a set of overarching principles and recommendations. We hope that the current recommendations will be broadly applied in clinical practice and/or serve as a template for national societies to develop local recommendations.

    更新日期:2019-12-17
  • 2018 Update of the EULAR recommendations for the management of large vessel vasculitis
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Bernhard Hellmich; Ana Agueda; Sara Monti; Frank Buttgereit; Hubert de Boysson; Elisabeth Brouwer; Rebecca Cassie; Maria C Cid; Bhaskar Dasgupta; Christian Dejaco; Gulen Hatemi; Nicole Hollinger; Alfred Mahr; Susan P Mollan; Chetan Mukhtyar; Cristina Ponte; Carlo Salvarani; Rajappa Sivakumar; Xinping Tian; Gunnar Tomasson; Carl Turesson; Wolfgang Schmidt; Peter M Villiger; Richard Watts; Chris Young; Raashid Ahmed Luqmani

    Background Since the publication of the European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis (LVV) in 2009, several relevant randomised clinical trials and cohort analyses have been published, which have the potential to change clinical care and therefore supporting the need to update the original recommendations. Methods Using EULAR standardised operating procedures for EULAR-endorsed recommendations, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 13 countries. We modified existing recommendations and created new recommendations. Results Three overarching principles and 10 recommendations were formulated. We recommend that a suspected diagnosis of LVV should be confirmed by imaging or histology. High dose glucocorticoid therapy (40–60 mg/day prednisone-equivalent) should be initiated immediately for induction of remission in active giant cell arteritis (GCA) or Takayasu arteritis (TAK). We recommend adjunctive therapy in selected patients with GCA (refractory or relapsing disease, presence of an increased risk for glucocorticoid-related adverse events or complications) using tocilizumab. Methotrexate may be used as an alternative. Non-biological glucocorticoid-sparing agents should be given in combination with glucocorticoids in all patients with TAK and biological agents may be used in refractory or relapsing patients. We no longer recommend the routine use of antiplatelet or anticoagulant therapy for treatment of LVV unless it is indicated for other reasons. Conclusions We have updated the recommendations for the management of LVV to facilitate the translation of current scientific evidence and expert opinion into better management and improved outcome of patients in clinical practice.

    更新日期:2019-12-17
  • 2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Pascal Richette; Michael Doherty; Eliseo Pascual; Victoria Barskova; Fabio Becce; Johann Castaneda; Malcolm Coyfish; Sylvie Guillo; Tim Jansen; Hein Janssens; Frédéric Lioté; Christian D Mallen; George Nuki; Fernando Perez-Ruiz; José Pimentao; Leonardo Punzi; Anthony Pywell; Alexander K So; Anne-Kathrin Tausche; Till Uhlig; Jakub Zavada; Weiya Zhang; Florence Tubach; Thomas Bardin

    Although gout is the most common inflammatory arthritis, it is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since the first EULAR recommendations for the diagnosis of gout in 2006. This prompted a systematic review and update of the 2006 recommendations. A systematic review of the literature concerning all aspects of gout diagnosis was performed. Recommendations were formulated using a Delphi consensus approach. Eight key recommendations were generated. A search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definite diagnosis of gout. There was consensus that a number of suggestive clinical features support a clinical diagnosis of gout. These are monoarticular involvement of a foot or ankle joint (especially the first metatarsophalangeal joint); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling; erythema; male gender and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it is recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of MSU crystal deposition (double contour sign and tophi). There was consensus that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all people with gout should be systematically assessed for presence of associated comorbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed.

    更新日期:2019-12-17
  • 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Victoria Furer; Christien Rondaan; Marloes W Heijstek; Nancy Agmon-Levin; Sander van Assen; Marc Bijl; Ferry C Breedveld; Raffaele D'Amelio; Maxime Dougados; Meliha Crnkic Kapetanovic; Jacob M van Laar; A de Thurah; Robert BM Landewé; Anna Molto; Ulf Müller-Ladner; Karen Schreiber; Leo Smolar; Jim Walker; Klaus Warnatz; Nico M Wulffraat; Ori Elkayam

    To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

    更新日期:2019-12-17
  • 2019 EULAR recommendations for the generic core competences of health professionals in rheumatology
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Lisa Edelaar; Elena Nikiphorou; George E Fragoulis; Annamaria Iagnocco; Catherine Haines; Margot Bakkers; Lurdes Barbosa; Nada Cikes; Mwidimi Ndosi; Jette Primdahl; Yeliz Prior; Polina Pchelnikova; Valentin Ritschl; Valentin Sebastian Schäfer; Hana Smucrova; Inger Storrønning; Marco Testa; Dieter Wiek; Theodora P M Vliet Vlieland

    Background/objectives To maintain and optimise the quality of care provided by health professionals in rheumatology (HPRs), adequate educational offerings are needed. This task force (TF) aimed to develop evidence-based recommendations for the generic core competences of HPRs, with specific reference to nurses, physical therapists (PTs) and occupational therapists (OTs) to serve as a basis for their postgraduate education. Methods The EULAR standardised operating procedures for the development of recommendations were followed. A TF including rheumatologists, nurses, PTs, OTs, patient-representatives, an educationalist, methodologists and researchers from 12 countries met twice. In the first TF meeting, 13 research questions were defined to support a systematic literature review (SLR). In the second meeting, the SLR evidence was discussed and recommendations formulated. Subsequently, level of evidence and strength of recommendation were assigned and level of agreement (LoA) determined (0–10 rating scale). Results Three overarching principles were identified and 10 recommendations were developed for the generic core competences of HPRs. The SLR included 79 full-text papers, 20 of which addressed the competences, knowledge, skills, attitudes and/or educational needs of HPRs from multiple professions. The average LoA for each recommendation ranged from 9.42 to 9.79. Consensus was reached both on a research and educational agenda. Conclusion Evidence and expert opinion informed a set of recommendations providing guidance on the generic core competences of HPRs. Implementation of these recommendations in the postgraduate education of HPRs at the international and national level is advised, considering variation in healthcare systems and professional roles.

    更新日期:2019-12-17
  • 2018 update of the EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Bianca Bech; Jette Primdahl; Astrid van Tubergen; Marieke Voshaar; Heidi A Zangi; Lurdes Barbosa; Carina Boström; Boryana Boteva; Francesco Carubbi; Françoise Fayet; Ricardo J O Ferreira; Kirsten Hoeper; Agnes Kocher; Marja Leena Kukkurainen; Vivienne Lion; Patricia Minnock; Antonella Moretti; Mwidimi Ndosi; Milena Pavic Nikolic; Michael Schirmer; Hana Smucrova; Jenny de la Torre-Aboki; Jennifer Waite-Jones; Yvonne van Eijk-Hustings

    To update the European League Against Rheumatism (EULAR) recommendations for the role of the nurse in the management of chronic inflammatory arthritis (CIA) using the most up to date evidence. The EULAR standardised operating procedures were followed. A task force of rheumatologists, health professionals and patients, representing 17 European countries updated the recommendations, based on a systematic literature review and expert consensus. Higher level of evidence and new insights into nursing care for patients with CIA were added to the recommendation. Level of agreement was obtained by email voting. The search identified 2609 records, of which 51 (41 papers, 10 abstracts), mostly on rheumatoid arthritis, were included. Based on consensus, the task force formulated three overarching principles and eight recommendations. One recommendation remained unchanged, six were reworded, two were merged and one was reformulated as an overarching principle. Two additional overarching principles were formulated. The overarching principles emphasise the nurse’s role as part of a healthcare team, describe the importance of providing evidence-based care and endorse shared decision-making in the nursing consultation with the patient. The recommendations cover the contribution of rheumatology nursing in needs-based patient education, satisfaction with care, timely access to care, disease management, efficiency of care, psychosocial support and the promotion of self-management. The level of agreement among task force members was high (mean 9.7, range 9.6-10.0). The updated recommendations encompass three overarching principles and eight evidence-based and expert opinion-based recommendations for the role of the nurse in the management of CIA.

    更新日期:2019-12-17
  • EULAR points to consider for the use of big data in rheumatic and musculoskeletal diseases
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Laure Gossec; Joanna Kedra; Hervé Servy; Aridaman Pandit; Simon Stones; Francis Berenbaum; Axel Finckh; Xenofon Baraliakos; Tanja A Stamm; David Gomez-Cabrero; Christian Pristipino; Remy Choquet; Gerd R Burmester; Timothy R D J Radstake

    Background Tremendous opportunities for health research have been unlocked by the recent expansion of big data and artificial intelligence. However, this is an emergent area where recommendations for optimal use and implementation are needed. The objective of these European League Against Rheumatism (EULAR) points to consider is to guide the collection, analysis and use of big data in rheumatic and musculoskeletal disorders (RMDs). Methods A multidisciplinary task force of 14 international experts was assembled with expertise from a range of disciplines including computer science and artificial intelligence. Based on a literature review of the current status of big data in RMDs and in other fields of medicine, points to consider were formulated. Levels of evidence and strengths of recommendations were allocated and mean levels of agreement of the task force members were calculated. Results Three overarching principles and 10 points to consider were formulated. The overarching principles address ethical and general principles for dealing with big data in RMDs. The points to consider cover aspects of data sources and data collection, privacy by design, data platforms, data sharing and data analyses, in particular through artificial intelligence and machine learning. Furthermore, the points to consider state that big data is a moving field in need of adequate reporting of methods and benchmarking, careful data interpretation and implementation in clinical practice. Conclusion These EULAR points to consider discuss essential issues and provide a framework for the use of big data in RMDs.

    更新日期:2019-12-17
  • The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Zachary S Wallace; Ray P Naden; Suresh Chari; Hyon K Choi; Emanuel Della-Torre; Jean-Francois Dicaire; Phillip A Hart; Dai Inoue; Mitsuhiro Kawano; Arezou Khosroshahi; Marco Lanzillotta; Kazuichi Okazaki; Cory A Perugino; Amita Sharma; Takako Saeki; Nicolas Schleinitz; Naoki Takahashi; Hisanori Umehara; Yoh Zen; John H Stone

    IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises; existing literature; derivation and validation cohorts of 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiological and basic science investigations.

    更新日期:2019-12-17
  • Unmet need in rheumatology: reports from the Targeted Therapies meeting 2019
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Kevin L Winthrop; Michael E Weinblatt; Joan Bathon; Gerd R Burmester; Philip J Mease; Leslie Crofford; Vivian Bykerk; Maxime Dougados; James Todd Rosenbaum; Xavier Mariette; Joachim Sieper; Fritz Melchers; Bruce N Cronstein; Ferry C Breedveld; Joachim Kalden; Josef S Smolen; Daniel Furst

    Objectives To detail the greatest areas of unmet scientific and clinical needs in rheumatology. Methods The 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20–30 experts assigned to each group based on expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases. In each group, experts were asked to identify unmet clinical and translational research needs in general and then to prioritise and detail the most important specific needs within each disease area. Results Overarching themes across all disease states included the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world and ultimately to develop therapies that can cure inflammatory autoimmune diseases. Conclusions Unmet needs for new therapies and trial designs, particularly for those with treatment refractory disease, remain a top priority in rheumatology.

    更新日期:2019-12-17
  • Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Yoshiya Tanaka; Koji Oba; Takao Koike; Nobuyuki Miyasaka; Tsuneyo Mimori; Tsutomu Takeuchi; Shintaro Hirata; Eiichi Tanaka; Hidekata Yasuoka; Yuko Kaneko; Kosaku Murakami; Tomohiro Koga; Kazuhisa Nakano; Koichi Amano; Kazuyasu Ushio; Tatsuya Atsumi; Masayuki Inoo; Kazuhiro Hatta; Shinichi Mizuki; Shouhei Nagaoka; Shinichiro Tsunoda; Hiroaki Dobashi; Nao Horie; Norihiro Sato

    Objectives The aim of this study is to determine whether the ‘programmed’ infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year. Methods In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106. Results A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI −6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106. Conclusion Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.

    更新日期:2019-12-17
  • Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Toshihiro Kishikawa; Yuichi Maeda; Takuro Nii; Daisuke Motooka; Yuki Matsumoto; Masato Matsushita; Hidetoshi Matsuoka; Maiko Yoshimura; Shoji Kawada; Satoru Teshigawara; Eri Oguro; Yasutaka Okita; Keisuke Kawamoto; Shinji Higa; Toru Hirano; Masashi Narazaki; Atsushi Ogata; Yukihiko Saeki; Shota Nakamura; Hidenori Inohara; Atsushi Kumanogoh; Kiyoshi Takeda; Yukinori Okada

    Objective The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome’s role in RA pathology by a comprehensive metagenome-wide association study (MWAS). Methods We conducted MWAS of the RA gut microbiome in the Japanese population ( n case=82, n control=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis). Results Phylogenetic case–control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola ) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case–control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case–control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls. Conclusion Our shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome’s role in RA aetiology.

    更新日期:2019-12-17
  • FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Liang Kuang; Jiangyi Wu; Nan Su; Huabing Qi; Hangang Chen; Siru Zhou; Yan Xiong; Xiaolan Du; Qiaoyan Tan; Jing Yang; Min Jin; Fengtao Luo; Junjie Ouyang; Bin Zhang; Zuqiang Wang; Wanling Jiang; Liang Chen; Shuai Chen; Ziming Wang; Peng Liu; Liangjun Yin; Fengjin Guo; Chuxia Deng; Di Chen; Chuanju Liu; Yangli Xie; Zhenhong Ni; Lin Chen

    Objectives This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis. Methods Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and μCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis. Results R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice. Conclusions Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis.

    更新日期:2019-12-17
  • A head-to-head comparison of the efficacy and safety of ixekizumab and adalimumab in biological-naïve patients with active psoriatic arthritis: 24-week results of a randomised, open-label, blinded-assessor trial
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Philip J Mease; Josef S Smolen; Frank Behrens; Peter Nash; Soyi Liu Leage; Lingnan Li; Hasan Tahir; Melinda Gooderham; Eswar Krishnan; Hong Liu-Seifert; Paul Emery; Sreekumar G Pillai; Philip S Helliwell

    Objectives To compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological disease-modifying antirheumatic drug-naïve patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARDs). Methods Patients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI100). Major secondary objectives, also at week 24, were to evaluate whether IXE was: (1) non-inferior to ADA for achievement of ACR50 and (2) superior to ADA for PASI100 response. Additional PsA, skin, treat-to-target and quality-of-life outcome measures were assessed at week 24. Results The primary efficacy endpoint was met (IXE: 36%, ADA: 28%; p=0.036). IXE was non-inferior for ACR50 response (IXE: 51%, ADA: 47%; treatment difference: 3.9%) and superior for PASI100 response (IXE: 60%, ADA: 47%; p=0.001). IXE had greater response versus ADA in additional PsA, skin, nail, treat-to-target and quality-of-life outcomes. Serious adverse events were reported in 8.5% (ADA) and 3.5% (IXE) of patients. Conclusions IXE was superior to ADA in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to csDMARDs. Safety and tolerability for both biologicals were aligned with established safety profiles.

    更新日期:2019-12-17
  • Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy upon microbiome composition
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Jian Yin; Peter Richard Sternes; Mingbang Wang; Jing Song; Mark Morrison; Ting Li; Ling Zhou; Xin Wu; Fusheng He; Jian Zhu; Matthew A Brown; Huji Xu

    Objectives Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome. Methods The stools from a case–control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray. Results Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients. Conclusion These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.

    更新日期:2019-12-17
  • Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Jing He; Ruijun Zhang; Miao Shao; Xiaozhen Zhao; Miao Miao; Jiali Chen; Jiajia Liu; Xiaoying Zhang; Xia Zhang; Yuebo Jin; Yu Wang; Shilei Zhang; Lei Zhu; Alexander Jacob; Rulin Jia; Xujie You; Xue Li; Chun Li; Yunshan Zhou; Yue Yang; Hua Ye; Yanying Liu; Yin Su; Nan Shen; Jessy Alexander; Jianping Guo; Julian Ambrus; Xin Lin; Di Yu; Xiaolin Sun; Zhanguo Li

    Objectives Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebo-controlled trial is required to formally evaluate the safety and efficacy of low-dose IL-2 therapy. Methods A randomised, double-blind and placebo-controlled clinical trial was designed to treat 60 patients with active SLE. These patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 12 weeks, and were followed up for additional 12 weeks. IL-2 at a dose of 1 million IU or placebo was administered subcutaneously every other day for 2 weeks and followed by a 2-week break as one treatment cycle. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. The secondary endpoints were other clinical responses, safety and dynamics of immune cell subsets. Results At week 12, the SRI-4 response rates were 55.17% and 30.00% for IL-2 and placebo, respectively (p=0.052). At week 24, the SRI-4 response rate of IL-2 group was 65.52%, compared with 36.67% of the placebo group (p=0.027). The primary endpoint was not met at week 12. Low-dose IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus nephritis, compared with 16.67% (2/12) in the placebo group (p=0.036). No serious infection was observed in the IL-2 group, but two in placebo group. Besides expansion of regulatory T cells, low-dose IL-2 may also sustain cellular immunity with enhanced natural killer cells. Conclusions Low-dose IL-2 might be effective and tolerated in treatment of SLE. Trial registration number ClinicalTrials.gov Registries ([NCT02465580][1] and [NCT02932137][2]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02465580&atom=%2Fannrheumdis%2F79%2F1%2F141.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02932137&atom=%2Fannrheumdis%2F79%2F1%2F141.atom

    更新日期:2019-12-17
  • Antigen-driven selection of antibodies against SSA, SSB and the centromere ‘complex’, including a novel antigen, MIS12 complex, in human salivary glands
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Masaru Takeshita; Katsuya Suzuki; Yukari Kaneda; Humitsugu Yamane; Kazuhiro Ikeura; Hidekazu Sato; Shin Kato; Kazuyuki Tsunoda; Hisashi Arase; Tsutomu Takeuchi

    Objectives Recent evidences have revealed that anti-SSA/SSB antibodies, the major autoantibodies in Sjögren's syndrome (SS), are produced in salivary glands. This study aims to clarify overall of autoantibody production at lesion site, including anti-centromere antibody (ACA)-positive SS. Methods Antibodies of antibody-secreting cells in human salivary glands were produced as recombinant antibodies. The reactivity of these antibodies and their revertants were investigated by ELISA and newly developed antigen-binding beads assay, which can detect conformational epitopes. The target of uncharacterised antibodies was identified by immunoprecipitation and mass spectrometry. Autoantibody-secreting cells in salivary gland tissue were identified by immunohistochemistry using green fluorescent protein-autoantigen fusion proteins. Results A total of 256 lesion antibodies were generated, and 69 autoantibodies including 24 ACAs were identified among them. Beads assay could detect more autoantibodies than ELISA, suggesting autoantibodies target to antigens with native conformation. After somatic hypermutations were reverted, autoantibodies drastically decreased antigen reactivity. We showed that MIS12 complex, a novel target of ACA, and CENP-C are major targets of ACA produced in salivary glands by examining cloned antibodies and immunohistochemistry, whereas few anti-CENP-B antibodies were detected. The target profiling of serum ACA from 269 patients with SS, systemic sclerosis (SSc), primary biliary cirrhosis (PBC) and healthy controls revealed that ACA-positive patients have antibodies against various sites of centromere complex regardless of disease. Conclusion We showed direct evidences of antigen-driven maturation of anti-SSA/SSB antibody and ACA in SS lesion. ACA recognises centromere ‘complex’ rather than individual protein, and this feature is common among patients with SS, SSc and PBC.

    更新日期:2019-12-17
  • Irritable bowel syndrome symptoms in axial spondyloarthritis more common than among healthy controls: is it an overlooked comorbidity?
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Johan Karlsson Wallman; Elisabeth Mogard; Jan Marsal; Kristofer Andréasson; Anna Jöud; Mats Geijer; Lars Erik Kristensen; Elisabet Lindqvist; Tor Olofsson

    The link between spondyloarthritis and inflammatory bowel disease (IBD) is well-established, with 5%–10% of patients with axial spondyloarthritis (axSpA) having concurrent IBD. Beyond that, ~50%–60% display microscopic gut inflammation,1 and faecal calprotectin (F-calprotectin) is elevated,2 although neither of these findings have been clearly linked to gut symptoms.1 2 Nevertheless, >50% of patients with ankylosing spondylitis (AS) report frequent gut pain/diarrhoea.3 This calls for investigating other potential causes, including irritable bowel syndrome (IBS), for which data in axSpA remain sparse. IBS (general population prevalence ~11%4) is thought to arise through mechanisms similar to fibromyalgia, common in axSpA (affecting up to 25% versus ~2% in the general population). We aimed to compare the prevalence of gut symptoms meeting ROME III criteria for IBS between patients with axSpA and healthy controls.5 Hence, 182 consecutive patients with well-characterised axSpA without known IBD from the population-based SPARTAKUS study,2 and 50 controls, frequency-matched for sex/age, without rheumatic disease or IBD, were included (online supplementary table S1). For SPARTAKUS protocol/classification algorithm details, see online supplementary file 1.### Supplementary data [annrheumdis-2019-216134supp001.pdf] We found that gut symptoms meeting IBS criteria were significantly more frequent among patients with axSpA (30%) than controls (16%; OR: 2.5 (95% CI 1.1 to 5.7); p=0.036) by sex/age-adjusted logistic regression (figure 1A). Additional adjustments for F-calprotectin levels and non-steroidal anti-inflammatory drug (NSAID)-use, respectively, as well as excluding patients/controls reporting ‘alarm symptoms’ (frequent bloody/black stools; unexplained weight-loss), yielded similar OR-estimates for the patients/controls difference (online supplementary file 1). Figure 1 Proportions of patients with axSpA and controls reporting gut symptoms …

    更新日期:2019-12-17
  • Both HLA class I and II regions identified as genome-wide significant susceptibility loci for adult-onset Still's disease in Chinese individuals
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Zhiqiang Li; Hong-Lei Liu; Jianhua Chen; Ting Zeng; Lin He; Meihang Li; Cainan Luo; Shuang Liu; Ting-Ting Ding; Kuerbanjiang Yimaiti; Jialin Teng; Xingwang Li; Yonghe Ding; Xiaobing Cheng; Juan Zhou; Junna Ye; Jue Ji; Yu-Tong Su; Hui Shi; Yue Sun; Chengwen Gao; Qiongyi Hu; Huihui Chi; Xuan Yuan; Zhuochao Zhou; Dong Wang; Ke Wang; Chang-Gui Li; Yuanchao Sun; Yujuan Niu; Lin-Jie Chen; Jian Xu; Lijun Wu; Zhaowei Zhou; Dun Pan; Haitao Niu; Yongyong Shi; Chengde Yang

    Adult-onset Still's disease (AOSD) is a rare autoinflammatory condition with unclear aetiology and highly heterogeneous manifestations, such as spiking fever, skin rash and arthralgia (or arthritis).1 2 AOSD is usually the result of both genetic and environmental factors. However, only a few genetic loci have been associated with AOSD, and none of them have reached the threshold for genome-wide significance (GWS) of p<5×10− 8.2 3 For example, HLA-DRB1 was strongly associated with AOSD in previous studies (the p value for the most significant association was 8.60×10− 6).3 HLA-DRB1 also influences the risk of systemic juvenile idiopathic arthritis (JIA),4 which presents similarly to AOSD but differs in age of onset. In addition, functional variations in periodic fever syndrome genes have been identified in some AOSD patients (Bonferroni corrected p values ranged from 2.34×10− 3 to 2.40×10− 4).5 In this study, for the first time, we conducted a genome-wide association study (GWAS) to systematically screen genetic factors influencing susceptibility to AOSD (online supplementary text). Principal component analysis was adopted to evaluate population stratification between cases and controls and to detect outliers for removal (online supplementary figure S1). After quality control and imputation, a total of 3 547 931 variants in 264 AOSD cases and 2420 controls (discovery: 247 cases vs 2163 controls; replication: 17 cases vs 257 controls; online supplementary text and table S1) from China …

    更新日期:2019-12-17
  • Molecular typing of cryoglobulins by mass spectrometry
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Adrian YS Lee; Tim Chataway; Thomas P Gordon; Jing Jing Wang

    A cause of potentially devastating pathologies, cryoglobulins are immunoglobulin complexes that precipitate out of serum at temperatures lower than 37°C. They often arise secondary to underlying conditions, such as hepatitis infections, although may be idiopathic. Brouet et al 1 classified cryoglobulins according to their immunoglobulin composition: type I (monoclonal), type II (mixed with monoclonal rheumatoid factor (RF)) and type III (mixed with polyclonal RF). Detection of cryoglobulins has not changed in decades and as a multistep process, is fraught with problems and a lack of universal standardisation to preanalytic handling. Currently, electrophoresis and immunofixation methods are used to characterise cryoglobulins. These techniques are unable to resolve and track specific clonotypes which can mutate and change pathogenicity over time. Mass spectrometry (MS) may be used to molecularly type IgM RFs in cryoglobulins.2 Using an MS-based proteomic approach, we recently identified the immunoglobulin heavy chain variable region (IGHV) subfamilies and mutational …

    更新日期:2019-12-17
  • Dysfunctional missense variant of OAT10/SLC22A13 decreases gout risk and serum uric acid levels
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Toshihide Higashino; Keito Morimoto; Hirofumi Nakaoka; Yu Toyoda; Yusuke Kawamura; Seiko Shimizu; Takahiro Nakamura; Kazuyoshi Hosomichi; Akiyoshi Nakayama; Keiko Ooyama; Hiroshi Ooyama; Toru Shimizu; Miki Ueno; Toshimitsu Ito; Takashi Tamura; Mariko Naito; Hiroshi Nakashima; Makoto Kawaguchi; Mikiya Takao; Yosuke Kawai; Naoki Osada; Kimiyoshi Ichida; Ken Yamamoto; Hiroshi Suzuki; Nariyoshi Shinomiya; Ituro Inoue; Tappei Takada; Hirotaka Matsuo

    Organic anion transporter 10 (OAT10), also known as SLC22A13, has hitherto been identified as a urate transporter by in vitro analyses.1 Despite the reported expression of OAT10 on the apical membrane of the renal proximal tubular cells,1 the physiological impact of OAT10 on urate handling in humans remains to be elucidated. Accumulating evidence suggests that functional variants of already-characterised, physiologically important urate transporters—URAT1/SLC22A12, GLUT9/SLC2A9, BCRP/ABCG2 and NPT1/SLC17A1—affect serum uric acid (SUA) levels and susceptibility of gout,2–6 the most common form of inflammatory arthritis. However, there are no reports on the association between OAT10 gene and either hyperuricaemia or gout. Here, for the first time, we reveal that a dysfunctional variant of OAT10 decreases both gout risk and SUA levels, suggesting OAT10 to be physiologically involved in urate reabsorption in the human kidney, as described below. To explore exonic variants in OAT10 potentially associated with gout susceptibility, we sequenced all exons of OAT10 in 480 gout cases and 480 controls of Japanese male6 and conducted an association analysis (see online supplementary tables S1 and S2), followed by a replication study on 924 gout cases and 2113 controls (see online supplementary figure S1). In two identified OAT10 variants with minor allele frequency (MAF) >0.5%, only rs117371763 (c.1129C>T; p.Arg377Cys [R377C]) was significantly associated with gout susceptibility after Bonferroni correction (p=0.014). The significant association between rs117371763 and gout susceptibility was replicated, and our meta-analysis showed a significant protective effect of rs117371763 on gout susceptibility (OR=0.67; 95% CI 0.53 to 0.85; pmeta …

    更新日期:2019-12-17
  • Imputation-based analysis of MICA alleles in the susceptibility to ankylosing spondylitis
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Xiaodong Zhou; John D Reveille

    A recent study has raised new questions about the independent association of MICA alleles with ankylosing spondylitis (AS).1 This letter highlights some important issues to be discussed in response to this article. The authors used imputation to genotype MICA and HLA-B27 in patients with AS and controls of European ancestry. The results appeared discordant with the previous report that showed a strong and human leukocyte antigen (HLA)-B27 independent association between MICA*007:01 and AS in US and Chinese cohorts.2 A common finding was a significant high rate of MICA*007 in patient with AS. The …

    更新日期:2019-12-17
  • Response to: Imputation-based analysis of MICA alleles in the susceptibility to ankylosing spondylitis by Zhou et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Adrian Cortes; Matthew A Brown

    To the Editor, As Zhou and Reveille note,1 MICA is a functionally enticing candidate gene for ankylosingspondylitis (AS). It is however challenging to study because of the technical difficulty of direct genotyping studies of the locus, its proximity and strong linkage disequilibrium with HLA-B , and the fact that it is subject to major population stratification effects. We recently performed an association study of common MICA alleles with AS susceptibility and observed no evidence of association in either HLA-B*27 positive or negative stratified analyses.2 In this study, …

    更新日期:2019-12-17
  • ANA testing in ‘real life’
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Maria Infantino; Mariangela Manfredi; Paolo Soda; Mario Merone; Antonella Afeltra; Amelia Rigon

    The recent article by Pisetsky et al 1 showing data derived from a comparison of different antinuclear antibody (ANA) assays in a cohort of patients with established systemic lupus erythematosus highlighted the critical issue of ANA detection. With great interest, we read the correspondence by van Hoovels et al 2 describing variation in ANA detection by automated indirect immunofluorescence (IIF) analysis and the following letter from Mahler and Auza on the strong need for ANA testing standardisation.3 Nowadays, the IIF on human epithelial cells (HEp-2) is considered the gold standard for ANA testing, but biological and non-biological issues limiting the IIF test are not currently adequately clarified in study literature.4 5 In fact, despite the fact that the IIF method on HEp-2 cells has existed for about 40 years, there are little data on this topic, and studies are mainly focused on selected patient groups, rather than samples from ‘real …

    更新日期:2019-12-17
  • Response to: ‘ANA testing in “real life”’ by Infantino et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    David S Pisetsky; Diane M Spencer; Peter E Lipsky; Brad H Rovin

    We thank Dr Infantino and colleagues for their comments1 on our paper on assay variability in antinuclear antibody (ANA) testing by indirect immunofluorescence (IIF)2 and subsequent communications that have been published in the journal.3–7 We agree with their observations on assay variability as well as the potential role of computer-aided diagnosis in improving IIF determinations. The issue of titre is also important, although changing the …

    更新日期:2019-12-17
  • Harmonisation of laboratory tests for rheumatic diseases: still a long way to go
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Lieve Van Hoovels; Xavier Bossuyt

    Antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), rheumatoid factor (RF) and antibodies to citrullinated peptides (ACPA) are widely used laboratory markers to support the diagnosis of ANA-associated systemic rheumatic diseases, ANCA-associated vasculitis and rheumatoid arthritis. Despite the fact that these tests are broadly used, they all suffer from a lack of harmonisation. Pisetsky et al 1 recently reported on assay variation in the detection of ANAs in the sera of patients with established systemic lupus erythematosus. Differences in ANA reactivity were found between different indirect immunofluorescence (IIF) methods and between IIF and immunoassays. Infantino et al 2 further stressed (1) that such …

    更新日期:2019-12-17
  • Antinuclear autoantibodies: discordance among four different assays
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Yovana Pacheco; Diana M Monsalve; Yeny Acosta-Ampudia; Cilia Rojas; Juan-Manuel Anaya; Carolina Ramírez-Santana

    Detection of antinuclear antibodies (ANAs) is of paramount importance for diagnosis and assessment of autoimmune diseases (ADs), but may vary depending on the method used. Therefore, we aimed to compare three different line immunoassays (LIAs) for ANAs testing in order to simultaneously evaluate their concordance with the results obtained by a well known and widely used ELISA. Sera from women with established systemic lupus erythematosus (SLE, n=62) and Sjogren’s syndrome (SS, n=28) were examined. Patients with SLE had an average age of 48.7 years (IQR 36.8–57.0) with a disease duration of 14.8 years (IQR 9.0–18.0). Patients with SS had an average age of 62.1 years (IQR 55.5–71.0) with a duration of disease of 13.1 years (IQR 8.3–17). Table 1 shows the results from the two-by-two comparison for the four techniques. Different levels of agreement were observed among the assays. In general, they were deficient. The analysis showed only one ‘strong’ level of agreement between ELISA and IMTEC-ANA-LIA Maxx for anti-Ro measurement. Out of 39 comparisons, 14 did …

    更新日期:2019-12-17
  • Response to: “Antinuclear autoantibodies: discordance among four different assays” by Pacheco et al
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    David S Pisetsky; Diane M Spencer; Peter E Lipsky; Brad Rovin

    We thank Dr Pacheco and colleagues for their comments1 on our article2 on the variation of testing for antinuclear antibodies (ANA) by indirect immunofluorescence (IIF) in the context of systemic lupus erythematosus (SLE). Along with findings described in other letters,3–8 the observations by Pacheco and colleagues on three different line immunoassays (LIA) and an ELISA indicate that, as in the case of other technologies, LIAs can show considerable discordance among different kits that are currently available. This study also shows that results by LIA can differ from those obtained by an ELISA. Differences among ANA tests can have a variety of causes including assay conditions as well as the origin and biochemical properties of test antigens. …

    更新日期:2019-12-17
  • Biomarkers: to be or not to be
    Ann. Rheum. Dis. (IF 14.299) Pub Date : 2020-01-01
    Sule Yavuz; Lars Rönnblom

    We read with great interest the article by van den Hoogen et al 1 describing galectin-9 (Gal-9) as a novel, easy-to-measure biomarker for the interferon (IFN) signature in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). We support the views expressed by the authors that IFN signature is an important biomarker in disease activity in SLE and there is certainly a need for easier to measure biomarkers for IFN signature, but to suggest that Gal-9 could aid in clinical decision making in steering anti-IFN therapy seems premature. We know that the common …

    更新日期:2019-12-17
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