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  • Improvement of symptoms in clinically suspect arthralgia and resolution of subclinical joint inflammation: a longitudinal study in patients that did not progress to clinical arthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-16
    Robin M. ten Brinck; Debbie M. Boeters; Hanna W. van Steenbergen; Annette H. M. van der Helm-van Mil

    Arthralgia and MRI-detected subclinical inflammation can precede the development of clinically evident rheumatoid arthritis (RA). However, part of the patients presenting with clinically suspect arthralgia (CSA) do not progress to RA. In these ‘non-progressors’, we aimed to study the frequencies of spontaneous improvement of arthralgia and its relation with the course of subclinical inflammation. Between April 2012 and April 2015, 241 patients were considered at risk for RA based on the clinical presentation and included in the CSA cohort. One hundred fifty-two patients with complete data on clinical follow-up did not develop clinical arthritis, of which 98 underwent serial 1.5T MRI scans (wrist, MCP2–5, and MTP1–5 joints) at baseline and after 2 years. MRI scans were scored for synovitis, tenosynovitis, and bone marrow oedema (summed: MRI inflammation score). MRI scores were compared to scores of symptom-free persons. After a 2-year follow-up, 33% of the ‘non-progressors’ had complete resolution of symptoms; 67% had no symptom resolution and were diagnosed as persistent CSA (44%), osteoarthritis (10%), and tendinomuscular complaints (13%). With symptom-free controls as a reference, patients without resolution did not have increased MRI scores at any time point. However, patients achieving resolution of symptoms had increased MRI inflammation scores at baseline (4.0 vs. 2.6, p = 0.037), but not after 2 years (3.0 vs. 2.6; p = 0.57), and during follow-up, their MRI inflammation score decreased significantly (p = 0.036). A subgroup of CSA patients that did not progress to RA had spontaneous improvement of symptoms and resolution of subclinical joint inflammation. This time relationship suggests that symptoms and inflammation were causally related in these patients. Further research is needed to identify the mechanisms underlying the resolution of inflammation.

    更新日期:2020-01-17
  • Validation of prediction models of severe disease course and non-achievement of remission in juvenile idiopathic arthritis part 2: results of the Nordic model in the Canadian cohort
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-15
    Andrew Henrey; Veronika Rypdal; Martin Rypdal; Thomas Loughin; Ellen Nordal; Jaime Guzman

    Validated clinical prediction models to identify children with poor prognosis at the time of juvenile idiopathic arthritis (JIA) diagnosis would be very helpful for tailoring treatments, and avoiding under- or over-treatment. Our objective was to externally validate Nordic clinical prediction models in Canadian patients with JIA. We used data from 513 subjects at the 3-year follow-up from the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort. The predicted outcomes were non-achievement of remission, severe disease course, and functional disability. The Nordic models were evaluated exactly as published and after fine-tuning the logistic regression coefficients using multiple data splits of the Canadian cohort. Missing data was handled with multiple imputation, and prediction ability was assessed with C-indices. C-index values > 0.7 were deemed to reflect helpful prediction. Overall, 81% of evaluable patients did not achieve remission off medications, 15% experienced a severe disease course, and 38% reported disability (CHAQ score > 0). The Nordic model for predicting non-achievement of remission had a C-index of 0.68 (95% CI 0.62–0.74), and 0.74 (0.67–0.80) after fine-tuning. For prediction of severe disease course, it had a C-index of 0.69 (0.61–0.78), and 0.79 (0.68–0.91) after fine-tuning. The fine-tuned Nordic model identified 85% of the cohort as low risk for a severe disease course (< 20% chance) and 7% as high risk (> 60% chance). The Nordic model to predict functional disability had a C-index of 0.57 (0.50–0.63), and 0.51 (0.39–0.63) after fine-tuning. Fine-tuned Nordic models, combining active joint count, physician global assessment of disease activity, morning stiffness, and ankle involvement, predicted well non-achievement of remission and severe disease course in Canadian patients with JIA. The Nordic model for predicting disability could not predict functional disability in Canadian patients.

    更新日期:2020-01-15
  • Combatting joint pain and inflammation by dual inhibition of monoacylglycerol lipase and cyclooxygenase-2 in a rat model of osteoarthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-14
    Holly T. Philpott; Jason J. McDougall

    Endocannabinoids are showing great promise as effective mediators for controlling joint inflammation and pain. One strategy that could be harnessed to promote endogenous cannabinoid function is to inhibit the enzymatic break down of endocannabinoids locally in the joint. KML29 is an inhibitor of monoacylglycerol lipase (MAGL) activity which has been shown to promote increased 2-arachodonylglycerol (2-AG) levels in the circulation and in peripheral tissues. It is also known that 2-AG can be metabolised via the cyclo-oxygenase-2 (COX-2) pathway leading to the production of pro-inflammatory prostaglandins, which may counteract the effects of 2-AG. Therefore, this study examined the effect of KML29 alone as well as in combination with low-dose celecoxib (CXB) on joint pain and inflammation in the monoiodoacetate (MIA) model of osteoarthritis (OA) pain. Injection of MIA (3 mg) into the knee joints of male Wistar rats was used to model OA pain, inflammation, and nerve damage. Pain behaviour was assessed by von Frey hair algesiometry, and inflammation was evaluated using intravital microscopy to measure leukocyte trafficking in the synovial microvasculature. Intra-articular injection of MIA produced mechanical hypersensitivity as measured by von Frey hair algesiometry. Local injection of KML29 (700 μg) reduced joint pain at day 14 post-MIA induction, and this analgesic effect was blocked by the cannabinoid receptor antagonists AM281 and AM630 (P < 0.0001; n = 6). During the acute inflammatory phase of the MIA model (day 1), a significant reduction in withdrawal threshold (P < 0.0001; n = 6–8) and leukocyte trafficking was seen after treatment with KML29 + CXB (P < 0.0001; n = 6–8). Early treatment of MIA-injected knees (days 1–3) with KML29 + CXB ameliorated the development of mechanical secondary allodynia (P < 0.0001; n = 8) in the later stages of the MIA model. Combination therapy of KML29 plus CXB reduced joint pain and inflammation. Thus, dual inhibition of MAGL and cyclooxygenase-2 pathways could be a useful approach to alleviate joint inflammation and pain in OA joints.

    更新日期:2020-01-15
  • Correction to: Management of adult-onset Still’s disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-09
    Serena Colafrancesco; Maria Manara; Alessandra Bortoluzzi; Teodora Serban; Gerolamo Bianchi; Luca Cantarini; Francesco Ciccia; Lorenzo Dagna; Marcello Govoni; Carlomaurizio Montecucco; Roberta Priori; Angelo Ravelli; Paolo Sfriso; Luigi Sinigaglia

    Following publication of the original article [1], it was brought to our attention that the AOSD Consensus Group was incorrectly tagged and therefore not searchable. The publishers apologize for this error.

    更新日期:2020-01-11
  • Identifying clinical subgroups in IgG4-related disease patients using cluster analysis and IgG4-RD composite score
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-10
    Jieqiong Li; Yu Peng; Yuelun Zhang; Panpan Zhang; Zheng Liu; Hui Lu; Linyi Peng; Liang Zhu; Huadan Xue; Yan Zhao; Xiaofeng Zeng; Yunyun Fei; Wen Zhang

    To explore the clinical patterns of patients with IgG4-related disease (IgG4-RD) based on laboratory tests and the number of organs involved. Twenty-two baseline variables were obtained from 154 patients with IgG4-RD. Based on principal component analysis (PCA), patients with IgG4-RD were classified into different subgroups using cluster analysis. Additionally, IgG4-RD composite score (IgG4-RD CS) as a comprehensive score was calculated for each patient by principal component evaluation. Multiple linear regression was used to establish the “IgG4-RD CS” prediction model for the comprehensive assessment of IgG4-RD. To evaluate the value of the IgG4-RD CS in the assessment of disease severity, patients in different IgG4-RD CS groups and in different IgG4-RD responder index (RI) groups were compared. PCA indicated that the 22 baseline variables of IgG4-RD patients mainly consisted of inflammation, high serum IgG4, multi-organ involvement, and allergy-related phenotypes. Cluster analysis classified patients into three groups: cluster 1, inflammation and immunoglobulin-dominant group; cluster 2, internal organs-dominant group; and cluster 3, inflammation and immunoglobulin-low with superficial organs-dominant group. Moreover, there were significant differences in serum and clinical characteristics among subgroups based on the CS and RI scores. IgG4-RD CS had a similar ability to assess disease severity as RI. The “IgG4-RD CS” prediction model was established using four independent variables including lymphocyte count, eosinophil count, IgG levels, and the total number of involved organs. Our study indicated that newly diagnosed IgG4-RD patients could be divided into three subgroups. We also showed that the IgG4-RD CS had the potential to be complementary to the RI score, which can help assess disease severity.

    更新日期:2020-01-11
  • Comparison of performance of specific (SLEQOL) and generic (SF36) health-related quality of life questionnaires and their associations with disease status of systemic lupus erythematosus: a longitudinal study
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-10
    Worawit Louthrenoo; Nuntana Kasitanon; Eric Morand; Rangi Kandane-Rathnayake

    The utility of generic health-related quality of life (HRQoL) questionnaires in patients with systemic lupus erythematosus (SLE) is uncertain. We compared the performance of generic (SF36) and specific (SLEQOL) HRQoL surveys by examining their associations with the Global Rating of Change (GRC) and SLE clinical indicators. The study included SLE patients who attended a single-center rheumatology clinic between 2013 and 2017. Patients completed both specific (SLEQOL) and generic (SF36) surveys and rated their GRC compared to the previous visit using a 7-point Likert scale on the same day of routine visits. Based on GRC scores, patients’ change in HRQoL was categorized as “no change,” “deterioration,” or “improvement.” Disease activity (SLEDAI-2K), flare, and lupus low disease activity state (LLDAS) were assessed at each visit, and organ damage (SDI) was determined annually. Pairwise correlations between SLEQOL and SF36 components were examined, and associations between GRC status and SLE disease indicators were compared using generalized estimating equations (GEE). Three hundred thirty-seven patients with 2062 visits were included in the analysis. SLEQOL correlated significantly with SF36. Patients reported improvements in HRQoL in 58%, deterioration in 15%, and “no change” in 27% of all visits. Compared to the “no change” group, mean SF36 and SLEQOL scores were significantly lower in the deterioration group and higher in the improvement group. The magnitude of changes observed with SLEQOL and SF36 in the deterioration and improvement groups was similar. Patients in LLDAS had significantly higher mean scores in both SLEQOL and SF36. In contrast, patients with active disease, especially those with cutaneous, renal, central nervous system, and musculoskeletal activity, had significantly lower SLEQOL and SF36. Flare and organ damage were also associated with lower SLEQOL and SF36-PCS (physical component) but not with SF36-MCS (mental component). SLEQOL and SF36 similarly describe HRQoL in SLE. Both instruments demonstrated strong associations with GRC-based deterioration or improvement as well as SLE disease status. LLDAS was associated with improved HRQoL.

    更新日期:2020-01-11
  • Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-08
    Alain Meyer; Yves Troyanov; Julie Drouin; Geneviève Oligny-Longpré; Océane Landon-Cardinal; Sabrina Hoa; Baptiste Hervier; Josiane Bourré-Tessier; Anne-Marie Mansour; Sara Hussein; Vincent Morin; Eric Rich; Jean-Richard Goulet; Sandra Chartrand; Marie Hudson; Jessica Nehme; Jean-Paul Makhzoum; Farah Zarka; Edith Villeneuve; Jean-Pierre Raynauld; Marianne Landry; Erin K. O’Ferrall; Jose Ferreira; Benjamin Ellezam; Jason Karamchandani; Sandrine Larue; Rami Massie; Catherine Isabelle; Isabelle Deschênes; Valérie Leclair; Hélène Couture; Ira N. Targoff; Marvin J. Fritzler; Jean-Luc Senécal

    To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies. A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment. While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.

    更新日期:2020-01-08
  • Barriers to treatment optimization and achievement of patients’ goals: perspectives from people living with rheumatoid arthritis enrolled in the ArthritisPower registry
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-07
    Kelly Gavigan; W. Benjamin Nowell; Mylene S. Serna; Jeffrey L. Stark; Mohamed Yassine; Jeffrey R. Curtis

    Few studies have investigated patients’ own treatment goals in rheumatoid arthritis (RA). The objective of this real-world, cross-sectional study of US patients with RA was to identify factors that patients believed influenced their physician’s treatment decisions. Secondary objectives included reasons patients tolerated sub-optimal disease control and their perceived barriers to treatment optimization. Eligible participants were enrolled in the ArthritisPower registry, ≥ 19 years, had physician-diagnosed RA, unchanged treatment within 3 months of baseline, prior/current disease-modifying antirheumatic drug treatment (DMARDs), and computer/smartphone access. In December 2017, participants completed Patient-Reported Outcomes Measurement Information System-Computerized Adaptive Tests (PROMIS-CAT) for pain interference, fatigue, sleep disturbance, and physical function. Routine Assessment of Patient Index Data 3 (RAPID3) provided disease activity scores (0–30). Participants completed an online survey on barriers to treatment optimization, including self-perception of disease compared to RAPID3/PROMIS scores. A total of 249 participants met inclusion criteria and completed the survey. Mean age (SD) was 52 (11) years, and the majority were female (92%) with high RAPID3 disease activity (175/249 [70%]; median score 18). The main reason participants did not change treatment was their physician’s recommendation (66%; n = 32). Of participants with high RAPID3 disease activity, 66 (38%) were offered a treatment change; 19 (29%) of whom declined the change. Most participants who intensified treatment did so because their symptoms had remained severe or worsened (51%; n = 65); only 16 (25%) participants intensified because they had not reached a specified treatment goal. Among participants who self-reported their disease activity as “none/low” or “medium” (n = 202; 81% of cohort), most still had RAPID3 high disease activity (137/202 [68%]; score > 12). Most PROMIS scores showed moderate agreement with participants’ self-assessment of health status, in contrast to RAPID3 (weighted kappa: 0.05 [95% CI − 0.01, 0.11]). Most participants trusted their rheumatologist’s treatment decisions and prioritized their physician’s treatment goals over their own. Patients should be encouraged to share their treatment goals/expectations with their rheumatologist, in line with the treat-to-target approach. RAPID3 may be inappropriate for setting patient-centric treatment goals given the poor agreement with self-reported disease activity; most PROMIS scores showed better alignment with patients’ own assessments.

    更新日期:2020-01-07
  • Psychometric validation of the Hand Disability in Systemic Sclerosis-Digital Ulcers (HDISS-DU®) patient-reported outcome instrument
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-06
    Luc Mouthon; Serge Poiraudeau; Margaret Vernon; Kelly Papadakis; Loïc Perchenet; Dinesh Khanna

    We aimed to develop a patient-reported outcome measure, in accordance with the US Food and Drug Administration guidance, to capture the impact of systemic sclerosis-related digital ulcers (SSc-DUs) on hand function. Psychometric analyses were conducted to evaluate and document the measurement properties of the resulting instrument—the Hand Disability in Systemic Sclerosis-Digital Ulcers (HDISS-DU®). The HDISS-DU was developed through a series of confirmatory, qualitative concept-elicitation interviews (N = 36) to provide supportive evidence that the instrument captures all relevant issues and functional limitations relating to SSc-DUs in this patient population. Psychometric analyses used blinded data from two randomised, controlled, phase 3 trials in patients with SSc-DUs (N = 517). The analyses included assessment of reliability, construct validity, responsiveness and thresholds for meaningful change. Qualitative interviews confirmed that the HDISS-DU had good content coverage and patients understood the HDISS-DU instructions, items and response scale. The HDISS-DU demonstrated excellent internal consistency and test-retest reliability, with satisfactory construct validity. Overall, the HDISS-DU was highly responsive to change in digital ulcer severity: the no-change group (for other criterion measures) had mean differences and effect sizes close to 0, while mean differences were mostly negative (indicating improvement) for the improvement groups (for other criterion measures) and vice versa. The preliminary threshold for meaningful change was a 0.50 difference in HDISS-DU score. Using data from two large studies of SSc-DU patients, these psychometric analyses support the reliability, validity, discriminating ability and responsiveness to change of the HDISS-DU for evaluating treatment outcomes in future clinical studies and clinical practice.

    更新日期:2020-01-06
  • The importance of ultrasound in identifying and differentiating patients with early inflammatory arthritis: a narrative review
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-02
    Gurjit S. Kaeley; Catherine Bakewell; Atul Deodhar

    Early differentiation between different types of inflammatory arthritis and subsequent initiation of modern treatments can improve patient outcomes by reducing disease activity and preventing joint damage. Routine clinical evaluation, laboratory testing, and radiographs are typically sufficient for differentiating between inflammatory and predominantly degenerative arthritis (e.g., osteoarthritis). However, in some patients with inflammatory arthritis, these techniques fail to accurately identify the type of early-stage disease. Further evaluation by ultrasound imaging can delineate the inflammatory arthritis phenotype present. Ultrasound is a noninvasive, cost-effective method that enables the evaluation of several joints at the same time, including functional assessments. Further, ultrasound can visualize pathophysiological changes such as synovitis, tenosynovitis, enthesitis, bone erosions, and crystal deposits at a subclinical level, which makes it an effective technique to identify and differentiate most common types of inflammatory arthritis. Limitations associated with ultrasound imaging should be considered for its use in the differentiation and diagnosis of inflammatory arthritides.

    更新日期:2020-01-02
  • Association of circulating microRNAs with prevalent and incident knee osteoarthritis in women: the OFELY study
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2020-01-02
    Jean-Charles Rousseau; Marjorie Millet; Martine Croset; Elisabeth Sornay-Rendu; Olivier Borel; Roland Chapurlat

    In the context of the scarcity of biomarkers for knee osteoarthritis (OA), we examined the associations of prevalent and incident OA with the expression levels of serum miRNAs in subjects with and without OA. With a next-generation sequencing approach, we compared the miRome expression of 10 women with knee OA and 10 age-matched healthy subjects. By real-time qPCR, we analyzed the expression levels of 19 miRNAs at baseline selecting 43 women with prevalent knee OA (Kellgren Lawrence score of 2/3), 23 women with incident knee OA over a 4-year follow-up and 67 healthy subjects without prevalent or incident OA matched for age and body mass index. Serum miR-146a-5p was significantly increased in the group of prevalent knee OA compared with controls (relative quantification (RQ); median [Interquartile range] 1.12 [0.73; 1.46] vs 0.85 [0.62; 1.03], p = 0.015). The likelihood of prevalent knee OA was significantly increased (odds ratio [95% confidence interval (CI)] 1.83 [1.21–2.77], p = 0.004) for each quartile increase in serum miR-146a-5p. The women with miR-146a-5p levels above the median (0.851) had a higher risk of prevalent knee OA compared to those below the median [95% CI] 4.62 [1.85–11.5], p = 0.001. Moreover, we found a significant association between the baseline level of serum miR-186-5p and the risk of incident knee OA (Q4 vs Q1–3; odds ratio [95% CI] 6.13 [1.14–32.9], p = 0.034). We showed for the first time that miR-146a-5p and miR-186-5p are significantly associated with prevalent and incident knee OA, respectively.

    更新日期:2020-01-02
  • Significant association between clinical characteristics and changes in peripheral immuno-phenotype in large vessel vasculitis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-30
    Kotaro Matsumoto; Katsuya Suzuki; Keiko Yoshimoto; Noriyasu Seki; Hideto Tsujimoto; Kenji Chiba; Tsutomu Takeuchi

    Large vessel vasculitis (LVV) is a type of vasculitis characterized by granulomatous inflammation of medium- and large-sized arteries. Clinical assessment of acute phase reactants has been conventionally used to diagnose and monitor diseases; however, accurate assessment of vascular disease activity status can be difficult. In this study, we investigated comprehensive immuno-phenotyping to explore useful biomarkers associated with clinical characteristics. Consecutive patients with newly diagnosed LVV who visited our institution between May 2016 and May 2019 were enrolled. The number of circulating T cells, B cells, natural killer cells, dendritic cells, monocytes, and granulocytes was examined and chronologically followed. Baseline and time-course changes in immuno-phenotyping associated with disease activity were assessed. Comprehensive immuno-phenotyping data from 90 samples from each of 20 patients with LVV were compared with those from healthy controls (HCs). The number of helper T (Th), follicular helper T (Tfh), CD8+ T, CD14++ CD16+ monocytes, and neutrophils were higher in patients with giant cell arteritis (GCA) and/or Takayasu arteritis (TAK) than in HCs. Among them, the number of CD8+ T and CD8+ Tem were higher in patients with TAK than in GCA. Notably, memory CD4+ and CD8+ T cells in patients with TAK remained high even in the remission phase. Further analysis revealed that the number of Th1, Th17, and Tfh cells was associated with disease relapse in GCA and TAK and that the number of CD8+ T cells was associated with relapse in TAK. Th1, Th17, and Tfh cells decreased after treatment with biologic agents, while CD8+ T cells did not. Our results from peripheral immuno-phenotyping analysis indicate that the numbers of Th and Tfh cells changed along with the disease condition in both GCA and TAK, while that of CD8+ T cells did not, especially in TAK. Treatment with biologic agents decreased the proportion of Th and Tfh cells, but not CD8+ T cells, in the patients. Chronological immuno-phenotyping data explained the difference in therapeutic response, such as reactivities against biologics, between GCA and TAK.

    更新日期:2019-12-31
  • Rule-based and machine learning algorithms identify patients with systemic sclerosis accurately in the electronic health record
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-30
    Lia Jamian; Lee Wheless; Leslie J. Crofford; April Barnado

    Systemic sclerosis (SSc) is a rare disease with studies limited by small sample sizes. Electronic health records (EHRs) represent a powerful tool to study patients with rare diseases such as SSc, but validated methods are needed. We developed and validated EHR-based algorithms that incorporate billing codes and clinical data to identify SSc patients in the EHR. We used a de-identified EHR with over 3 million subjects and identified 1899 potential SSc subjects with at least 1 count of the SSc ICD-9 (710.1) or ICD-10-CM (M34*) codes. We randomly selected 200 as a training set for chart review. A subject was a case if diagnosed with SSc by a rheumatologist, dermatologist, or pulmonologist. We selected the following algorithm components based on clinical knowledge and available data: SSc ICD-9 and ICD-10-CM codes, positive antinuclear antibody (ANA) (titer ≥ 1:80), and a keyword of Raynaud’s phenomenon (RP). We performed both rule-based and machine learning techniques for algorithm development. Positive predictive values (PPVs), sensitivities, and F-scores (which account for PPVs and sensitivities) were calculated for the algorithms. PPVs were low for algorithms using only 1 count of the SSc ICD-9 code. As code counts increased, the PPVs increased. PPVs were higher for algorithms using ICD-10-CM codes versus the ICD-9 code. Adding a positive ANA and RP keyword increased the PPVs of algorithms only using ICD billing codes. Algorithms using ≥ 3 or ≥ 4 counts of the SSc ICD-9 or ICD-10-CM codes and ANA positivity had the highest PPV at 100% but a low sensitivity at 50%. The algorithm with the highest F-score of 91% was ≥ 4 counts of the ICD-9 or ICD-10-CM codes with an internally validated PPV of 90%. A machine learning method using random forests yielded an algorithm with a PPV of 84%, sensitivity of 92%, and F-score of 88%. The most important feature was RP keyword. Algorithms using only ICD-9 codes did not perform well to identify SSc patients. The highest performing algorithms incorporated clinical data with billing codes. EHR-based algorithms can identify SSc patients across a healthcare system, enabling researchers to examine important outcomes.

    更新日期:2019-12-31
  • Unique primed status of microglia under the systemic autoimmune condition of lupus-prone mice
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-30
    Atsushi Nomura; Daisuke Noto; Goh Murayama; Asako Chiba; Sachiko Miyake

    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies. This disease causes disabling neuropsychiatric symptoms even in the absence of apparent inflammation in the central nervous system (CNS), but the mechanisms involved remain unknown. Innate immune-mediated inflammation has attracted attention as a pathogenic mechanism in neuropsychiatric diseases. We investigated the CNS of lupus-prone mice focusing on innate immunity. Three strains of lupus-prone mice, FcγRIIB−/−Yaa, an F1 hybrid of NZB and NZW (NZB/NZW) mice, and MRL/Faslpr (MRL/lpr) mice were used to analyze CNS immunopathology. Flow cytometry analysis demonstrated the numbers of brain CD45+ cells were increased compared with controls in lupus-prone mice. Upregulation of MHC class I and PDCA1 was observed in microglia and CD11b+ myeloid cells of lupus-prone mice, indicating they were activated in response to interferons (IFN). Microglial gene expression analysis of FcγRIIB−/−Yaa mice revealed the upregulation of IFN-responsive genes and inflammation-related genes including Axl, Clec7a, and Itgax, which were previously reported in neurodegenerative conditions and primed conditions. Upregulated chemokine gene expressions including Ccl5 and Cxcl10 were concurrent with increased numbers of T cells and monocytes, especially Ly6Clo monocytes in the CNS. Upregulation of Axl, Clec7a, Itgax, Ccl5, and Cxcl10 was also observed in NZB/NZW mice, indicating common lupus pathology. The primed status of microglia in FcγRIIB−/−Yaa mice was also demonstrated by morphological changes such as enlarged cell bodies with hypertrophic processes, and hyperreactivity to lipopolysaccharide. Immunohistochemistry of FcγRIIB−/−Yaa mice indicated reactive responses of astrocytes and vascular endothelium. Behavioral studies of FcγRIIB−/−Yaa mice revealed depressive-like behavior and heat hyperalgesia in the forced swim test and the tail-flick test, respectively. Our data indicated that microglia in lupus exhibit a unique primed phenotype characterized by the upregulated expressions of neurodegeneration-related genes and IFN-responsive genes. Interaction with peripheral cells and brain resident cells was presumed to orchestrate neuroinflammation. Targeting innate immune cells, such as microglia and monocytes, may be a promising therapeutic approach for neuropsychiatric SLE.

    更新日期:2019-12-30
  • High risk of gastrointestinal hemorrhage in patients with systemic sclerosis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-26
    Yi-Ting Lin; Yun-Shiuan Chuang; Jiunn-Wei Wang; Ping-Hsun Wu

    Systemic sclerosis (SSc), a life-threatening autoimmune disease characterized by vasculopathy. Numerous SSc patients demonstrate gastrointestinal (GI) involvement but the delicate GI bleeding risk remains sparse. We aimed to explore the role of SSc in determining the long-term risk of GI bleeding, including bleedings of upper (peptic and non-peptic ulcers) and lower GI tracts. Patients with SSc diagnosis were identified from the Catastrophic Illness Patient Database and the National Health Insurance Research Database from 1998 to 2007. Each SSc patient was matched with five SSc-free individuals by age, sex, and index date. All individuals (case = 3665, control = 18,325) were followed until the appearance of a GI bleeding event, death, or end of 2008. A subdistribution hazards model was assessed to evaluate the GI bleeding risk with adjustments for age, sex, and time-dependent covariates, comorbidity, and medications. The incidence rate ratios of GI bleeding were 2.38 (95% confidence interval [CI], 2.02–2.79), 2.06 (95% CI, 1.68–2.53), and 3.16 (95% CI, 2.53–3.96) for over-all, upper, and lower GI bleeding events in SSc patients. In the competing death risk in the subdistribution hazards model with time-covariate adjustment, SSc was an independent risk factor for over-all GI bleeding events (subdistribution hazard ratio [sHR] 2.98, 95% CI, 2.21–4.02), upper GI bleeding events (sHR 2.80, 95% CI, 1.92–4.08), and lower GI bleeding events (sHR 3.93, 95% CI, 2.52–6.13). SSc patients exhibited a significantly higher risk of over-all and different subtype GI bleeding events compared with the SSc-free population. The prevention strategy is needed for these high GI bleeding risk groups.

    更新日期:2019-12-27
  • Predicting gastrointestinal and renal involvement in adult IgA vasculitis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-26
    Alojzija Hočevar; Matija Tomšič; Vesna Jurčić; Katja Perdan Pirkmajer; Žiga Rotar

    Immunoglobulin A vasculitis (IgAV) is still poorly defined in the adult population. We aimed to determine the predictors of gastrointestinal (GI) or renal involvement in adult IgAV. The prospective study included histologically proven adult IgAV cases diagnosed between January 2013 and July 2019 at our secondary/tertiary rheumatology center. We evaluated the role of clinical and the laboratory parameters as markers predicting the GI or renal involvement in IgAV, using the multiple logistic regression analysis. During the 79-month observation period, we identified 214 new adult IgAV cases (59.3% males, median (interquartile range) age 64.6 (57.2–76.7) years). The GI tract and renal involvement developed in 58 (27.1%) and 83 (38.8%) cases, respectively (concurrently in 26 (12.1%) cases). In the multivariate logistic regression analysis, generalized purpura (OR 6.74 (95%CI 3.18–14.31)), the pre-treatment neutrophil to lymphocyte ratio (NLR) > 3.5 (OR 2.78 (95%CI 1.34–5.75)), and elevated serum IgA levels (OR 0.40 (95%CI 0.20–0.79)) were extracted as factors associated with GI complications, whereas current smoking (OR 3.23 (95%CI 1.50–6.98)), generalized purpura (OR 1.98 (95%CI 1.08–3.61)), elevated serum IgA (OR 2.25 (95%CI 1.21–4.18)), NLR > 3.5 (OR 1.96 (95%CI 1.02–3.77)), and marginally age (1.02 (95%CI 1.01–1.04)) emerged as factors associated with renal complications. Generalized purpura and pre-treatment NLR predicted both GI and renal involvement, whereas active smoking was associated with renal involvement, and the serum IgA level had a divergent effect on renal and GI involvement in adult IgAV.

    更新日期:2019-12-27
  • Conferring extracellular matrix affinity enhances local therapeutic efficacy of anti-TNF-α antibody in a murine model of rheumatoid arthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-23
    Kiyomitsu Katsumata; Jun Ishihara; Kazuto Fukunaga; Ako Ishihara; Eiji Yuba; Erica Budina; Jeffrey A. Hubbell

    Although disease in a majority of rheumatoid arthritis (RA) patients is often initially limited to one or a few joints, currently approved medications including anti-tumor necrosis factor-α antibody (α-TNF) are injected systemically. Given that α-TNF systemic injection typically does not cure RA and involves risk of treatment-related adverse events, one possible approach to enhance therapeutic efficacy and reduce α-TNF systemic exposure is to retain the antibodies in arthritic joints after local administration. The aim of this study was to evaluate the approach of conferring extracellular matrix (ECM) binding affinity to α-TNF antibodies in a RA model. α-TNF was chemically conjugated with a promiscuous ECM-binding peptide derived from placenta growth factor 2 (PlGF-2123-144). The binding activity of PlGF-2123-144-conjugated α-TNF (PlGF-2123-144-α-TNF) against ECM proteins was assessed by ELISA and by immunostaining on human cartilage specimens. The effect of conjugation on antibody function was assessed as a neutralizing activity against osteoclast differentiation. Retention at the injection site and therapeutic efficacy of PlGF-2123-144-α-TNF were tested in a collagen antibody-induced arthritis (CAIA) model in the mouse. PlGF-2123-144 peptide conjugation conferred α-TNF with affinity to ECM proteins without impairment of antigen recognition. PlGF-2123-144-α-TNF locally injected at a paw in the CAIA model was retained for at least 96 h at the injection site, whereas unmodified α-TNF was dispersed rapidly after injection. Local treatment with unmodified α-TNF did not suppress the arthritis score relative to isotype controls. By contrast, local administration of PlGF-2123-144-α-TNF suppressed arthritis development almost completely in the treated paw even at a 1000× lower dose. These data demonstrate that retention of α-TNF in arthritic joints can suppress arthritis development and enhance therapeutic efficacy. This simple bioengineering approach of ECM-binding peptide conjugation offers a powerful and clinically translational approach to treat RA.

    更新日期:2019-12-23
  • Digital ulcers in systemic sclerosis: their epidemiology, clinical characteristics, and associated clinical and economic burden
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-23
    Kathleen Morrisroe; Wendy Stevens; Joanne Sahhar; Gene-Siew Ngian; Nava Ferdowsi; Catherine L. Hill; Janet Roddy; Jennifer Walker; Susanna Proudman; Mandana Nikpour

    To determine the frequency and clinical characteristics of systemic sclerosis-related digital ulcers, and associated direct health care costs, quality of life, and survival. Digital ulcers (DUs) were defined as an area with a visually discernible depth and a loss of continuity of epithelial coverage. DU severity was calculated based on the physician reported highest number of new DUs at clinical review (mild = 1–5 DUs, moderate 6–10 DUs, severe > 10 DUs). Healthcare use was captured through data linkage, wherein SSc clinical data captured prospectively in a dedicated clinical database were linked with health services databases to capture hospital admissions, emergency department (ED) presentations and ambulatory care (MBS) utilization and cost for the period 2008–2015. Healthcare cost determinants were estimated using logistic regression. Among 1085 SSc patients, 48.6% experienced a DU over a mean follow-up of 5.2 ± 2.5 years. Those who developed DUs were more likely to have diffuse disease subtype (34.9% vs 18.2%, p < 0.001), anti-Scl-70 antibody (18.9% vs 9.3%, p < 0.001), and a younger age at SSc onset (43.6 ± 13.9 vs 48.8 ± 14.0 years, p < 0.001) in addition to reduced health-related quality of life (HRQoL) measured by the SF-36 but without a significant impact on survival. SSc patients with a history of a DU utilized significantly more healthcare resources per annum than those without a DU, including hospitalizations, ED presentation, and ambulatory care services. Total healthcare services, excluding medications, were associated with an annual excess cost per DU patient of AUD$12,474 (8574-25,677), p < 0.001, driven by hospital admission and ED presentation costs. DUs place a large burden on the patient and healthcare system through reduced HRQoL and increased healthcare resource utilization and associated cost.

    更新日期:2019-12-23
  • Inhibition of Nrf2/HO-1 signaling leads to increased activation of the NLRP3 inflammasome in osteoarthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-23
    Zhuming Chen; Huan Zhong; Jinsong Wei; Sien Lin; Zhixian Zong; Fan Gong; Xinqia Huang; Jinhui Sun; Peng Li; Hao Lin; Bo Wei; Jiaqi Chu

    Osteoarthritis (OA) is an inflammatory disease of the joints that causes progressive disability in the elderly. Reactive oxygen species (ROS) play an important role in OA development; they may activate the NLRP3 inflammasome, thereby inducing the secretion of proinflammatory IL-1β and IL-18, leading to the aggravation of the downstream inflammatory response. Nrf2 is a key transcription factor that regulates the expression of antioxidant enzymes that protect against oxidative stress and tissue damage. We aimed to explore the underlying mechanism of OA development by investigating NLRP3, ASC, Nrf2, and HO-1 expression in synovia and their regulatory networks in OA. Human total knee replacement samples were subjected to histology and micro-CT analysis to determine the pathological changes in the cartilage and subchondral bone and to assess the expression of inflammation-related markers in the synovial tissue by immunohistochemistry (IHC), qRT-PCR, and Western blot. To investigate these pathological changes in an OA animal model, adult Sprague-Dawley rats were subjected to anterior cruciate ligament transection and medial meniscectomy. Articular cartilage and subchondral bone changes and synovial tissue were also determined by the same methods used for the human samples. Finally, SW982 cells were stimulated with lipopolysaccharide (LPS) as an in vitro inflammatory cell model. The correlation between NLRP3 and Nrf2 expression was confirmed by knocking down NLRP3 or Nrf2. Cartilage destruction and subchondral bone sclerosis were found in the OA patients and OA model rats. Significantly increased expression levels of NLRP3, ASC, Nrf2, and HO-1 were found in the synovial tissue from OA patients. NLRP3, ASC, Nrf2, and HO-1 expression in the synovium was also upregulated in the OA group compared with the sham group. Furthermore, the NLRP3, Nrf2, HO-1, IL-1β, and IL-18 expression in LPS-treated SW982 cells was increased in a dose-dependent manner. As expected, the expression of NLRP3 was upregulated, and the expression of IL-1β and IL-18 was downregulated after Nrf2 silencing. However, knocking down NLRP3 did not affect the expression of Nrf2. ROS-induced oxidative stress may be the main cause of NLRP3 inflammasome activation and subsequent release of downstream factors during OA development. Nrf2/HO-1 signaling could be a key pathway for the activation of the NLRP3 inflammasome, which may contribute to the progression of OA. Herein, we discovered a novel role of Nrf2/HO-1 signaling in the production of NLRP3, which may facilitate the prevention and treatment of OA.

    更新日期:2019-12-23
  • Native myeloperoxidase is required to make the experimental vasculitis model
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-21
    Mayu Nonokawa; Ku Suzuki; Hideyuki Hayashi; Yuka Nishibata; Sakiko Masuda; Daigo Nakazawa; Satoshi Tanaka; Utano Tomaru; Akihiro Ishizu

    Dear Editor, Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) is a pathogenic autoantibody [1]. Wistar-Kyoto (WKY) rats immunized with human native MPO produce anti-human MPO antibody cross-reactive with rat MPO, resulting in the development of MPO-ANCA-associated vasculitis (MPO-AAV) [2]. MPO is a heterotetramer composed of two light chains (14 kDa) and two heavy chains (59 kDa) [3]. In this study, we examined if immunization of WKY rats with the recombinant light chain of human MPO could induce MPO-AAV. WKY rats (4–5 weeks old) were immunized with the recombinant light chain of human MPO (1600 μg/kg; Cloud-Clone, Katy, TX, USA; group 1) or human native MPO (1600 μg/kg; RayBiotech, Peachtree Corners, GA, USA; group 2) on day 0. These rats were given an intraperitoneal injection of pertussis toxin (800 ng; Sigma-Aldrich, St. Louis, MO, USA) on days 0 and 2. A subgroup of group 1 was given an intraperitoneal injection of lipopolysaccharide (LPS; 100 μM/week; Sigma-Aldrich) through days 7 to 35. Urine samples were collected using a metabolic cage on day 40. All rats were euthanized on day 42. Flow cytometry (FCM) using human neutrophils demonstrated the presence of ANCA in sera of group 2 but not group 1 (Fig. 1a). Correspondingly, sera of group 2 but not group 1 induced neutrophil extracellular traps (NETs) from tumor necrosis factor (TNF)-primed neutrophils (Fig. 1b). Immunoblot of neutrophil lysates demonstrated that antibody reactive with the MPO light chain (14 kDa) was produced in group 1, whereas antibodies reactive with the MPO heavy chain (59 kDa) and light chain (14 kDa) were produced in group 2 (Fig. 1c). The collective findings indicated that the anti-MPO light chain antibody produced in group 1 did not bind to native MPO. Renal tissue damage represented by hematuria and erythrocyte casts in renal tubules was evident in group 2 but not group 1 regardless of the disease boost by LPS (Fig. 1d, e). The degree of pulmonary hemorrhage that represents capillaritis in the lungs tended to be severe in group 2 compared to group 1 (Fig. 1f). Fig. 1 Development of MPO-AAV. a ANCA detected by FCM. Human peripheral blood neutrophils were fixed with 4% paraformaldehyde, and then the plasma membrane of neutrophils was penetrated using permeabilization wash buffer (BioLegend, San Diego, CA, USA). Cells (1 × 106/ml) were allowed to react with 1:500 diluted rat sera for 30 min at room temperature (RT) followed by reaction with fluorescence-labeled secondary antibody. Concerning day 42 sera of group 1, the reactivity of 1:100 and 1:20 dilutions was also examined. To show the reactivity of anti-MPO heavy chain antibody to native MPO, a similar FCM was performed using the anti-MPO heavy chain monoclonal antibody (5 μg/ml; 4A4; Bio-Rad, Tokyo, Japan) as primary antibody and mouse IgG2b (5 μg/ml; BioLegend) as isotype control. b NET-forming neutrophils detected by FCM. Human peripheral blood neutrophils (1 × 106/ml) were treated with 5 ng/ml TNF-α for 15 min at 37 °C and then exposed to 10% rat sera. After incubation for 3 h at 37 °C, cells were next made to react with a plasma membrane-impermeable DNA-binding dye, SYTOX Green (Life Technologies, Carlsbad, CA, USA). After filtering out the debris with a mesh, the percolated cells were subjected for FCM. Histograms highlighted in green represent NET-forming neutrophils. The percentage of NET-forming neutrophils induced by group 2 sera was significantly higher than that induced by group 1 sera. c ANCA detected by immunoblotting. Lysates of human neutrophils boiled under reducing condition were electrophoresed (5 × 105 cells/lane) and then transferred to polyvinylidene difluoride membrane. After blocking the non-specific binding of antibodies, the membrane was incubated in diluted rat sera (day 42; group 1, 1:200 dilution; group 2, 1:1000 dilution) overnight at 4 °C. After rinsing with phosphate-buffered saline (PBS) with Tween 20 (PBS-T), the membrane was next incubated in the solution of horseradish peroxidase (HRP)-conjugated secondary antibody for 1 h at RT. After rinsing with PBS-T, the HRP activity on the membrane was detected by chemiluminescence using ImageQuant LAS 4000 (GE Healthcare, Little Chalfont, UK). Blue arrowhead, MPO heavy chain (59 kDa); red arrowheads, MPO light chain (14 kDa). d Degree of hematuria assessed at urine sampling immediately by a dipstick (Siemens Healthineers, Erlangen, Germany). e Degree of renal tissue damage. Erythrocyte casts (yellow arrowheads) were counted in the maximum longitudinal section of the kidney. f Degree of pulmonary hemorrhage. The foci of pulmonary hemorrhage were counted in the maximum longitudinal section of the lung. Mann-Whitney U test was applied for statistical analyses between two non-parametric groupsFull size image The majority of MPO-AAV patients produced MPO-ANCA that recognizes an epitope in the heavy chain of MPO, whereas a few number of patients produced MPO-ANCA against an epitope in the light chain of MPO [4, 5]. The collective findings suggested that the recombinant light chain of human MPO has a low potential to induce MPO-AAV in rats compared to native human MPO. The data sheets used and/or analyzed during the current study are available from the corresponding author on reasonable request. 1. Nakazawa D, Masuda S, Tomaru U, Ishizu A. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol. 2019;15(2):91–101. Article Google Scholar 2. Little MA, Smyth L, Salama AD, Mukherjee S, Smith J, Haskard D, et al. Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis. Am J Pathol. 2009;174(4):1212–20. Article Google Scholar 3. Fiedler TJ, Davey CA, Fenna RE. X-ray crystal structure and characterization of halide-binding sites of human myeloperoxidase at 1.8 A resolution. J Biol Chem. 2000;275(16):11964–71. Article Google Scholar 4. Suzuki K, Kobayashi S, Yamazaki K, Gondo M, Tomizawa K, Arimura Y, et al. Analysis of risk epitopes of anti-neutrophil antibody MPO-ANCA in vasculitis in Japanese population. Microbiol Immunol. 2007;51(12):1215–20. Article Google Scholar 5. Gou SJ, Xu PC, Chen M, Zhao MH. Epitope analysis of anti-myeloperoxidase antibodies in patients with ANCA-associated vasculitis. PLoS One. 2013;8(4):e60530. Article Google Scholar Download references Not applicable. Funding This work was supported by a grant from Ono Pharmaceutical (Osaka, Japan). Affiliations Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, 0600812, Japan Mayu Nonokawa , Ku Suzuki , Hideyuki Hayashi , Yuka Nishibata , Sakiko Masuda  & Akihiro Ishizu Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan Daigo Nakazawa Center for Cause of Death Investigation, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan Satoshi Tanaka Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan Utano TomaruAuthors Search for Mayu Nonokawa in: PubMed • Google Scholar Search for Ku Suzuki in: PubMed • Google Scholar Search for Hideyuki Hayashi in: PubMed • Google Scholar Search for Yuka Nishibata in: PubMed • Google Scholar Search for Sakiko Masuda in: PubMed • Google Scholar Search for Daigo Nakazawa in: PubMed • Google Scholar Search for Satoshi Tanaka in: PubMed • Google Scholar Search for Utano Tomaru in: PubMed • Google Scholar Search for Akihiro Ishizu in: PubMed • Google Scholar Contributions AI designed the study. MN, KS, HH, YN, SM, and AI acquired the data. All authors were involved in the interpretation of data and approval of the manuscript. UT and AI wrote the manuscript. Corresponding author Correspondence to Akihiro Ishizu. Ethics approval and consent to participate Experiments using rats were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals in Hokkaido University (Permission No. 15-0034). Experiments using human materials were permitted by the Ethics Committee of the Faculty of Health Sciences, Hokkaido University (Permission No. 18-34). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Nonokawa, M., Suzuki, K., Hayashi, H. et al. Native myeloperoxidase is required to make the experimental vasculitis model. Arthritis Res Ther 21, 296 (2019) doi:10.1186/s13075-019-2084-7 Download citation Received 01 September 2019 Accepted 05 December 2019 Published 21 December 2019 DOI https://doi.org/10.1186/s13075-019-2084-7

    更新日期:2019-12-21
  • Enhanced angiogenic function in response to fibroblasts from psoriatic arthritis synovium compared to rheumatoid arthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-21
    S. Fromm; C. C. Cunningham; M. R. Dunne; D. J. Veale; U. Fearon; S. M. Wade

    Angiogenesis is an early event in the pathogenesis of both psoriatic arthritis (PsA) and rheumatoid arthritis (RA); however, there are striking differences in blood vessel morphology and activation between the two arthropathies. The aim of this study was to assess if the PsA and RA joint microenvironments differentially regulate endothelial cell function. PsA and RA primary synovial fibroblasts (SFC) were isolated from synovial biopsies, grown to confluence, and supernatants harvested and termed ‘conditioned media’ (CM). Human umbilical vein endothelial cells (HUVEC) were cultured with PsA SFC or RA SFC-CM (20%). HUVEC tube formation, migration, and PBMC adhesion were assessed by matrigel tube formation, wound repair, and PBMC adhesion assays. HUVEC cell surface expression of ICAM, VCAM, and E-Selectin was assessed by flow cytometry. Transcriptome analysis of genes promoting angiogenesis was performed by real-time PCR. Finally, a MSD multiplex angiogenic assay was performed on PsA SFC and RA SFC supernatants. Macroscopic synovitis and vascularity were similar in PsA and RA patients; however, significant differences in vascular morphological pattern were recorded with tortuous, elongated vessels observed in PsA compared to straight regular branching vessels observed in RA. Transcriptome analysis showed strong upregulation of the pro-angiogenic signature in HUVEC primed with PsA SFC-CM compared to RA SFC-CM and basal control. In parallel, paired PsA SFC-CM significantly induced HUVEC tube formation compared to that of RA SFC-CM. Furthermore, PsA SFC-CM induced HUVEC migration was paralleled by a significant induction in VEGFA, PFKFB3, ICAM-1, and MMP3 mRNA expression. A significant increase in PBMC adhesion and cell surface expression of VCAM-1, ICAM-1, and E-Selectin expression was also demonstrated in PsA SFC-CM-primed HUVEC compared to RA SFC-CM. Finally, VEGF, TSLP, Flt-1, and Tie-2 expression was elevated in PsA SFC-CM compared to RA SFC-CM, with no significant difference in other pro-angiogenic mediators including MIP-3, bFGF, PIGF, and MCP-1. PsA SFC and RA SFC secreted factors differentially regulate endothelial cell function, with soluble mediators in the PsA joint microenvironment inducing a more pro-angiogenic phenotype compared to the RA.

    更新日期:2019-12-21
  • High-throughput sequencing of CD4+ T cell repertoire reveals disease-specific signatures in IgG4-related disease
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-19
    Liwen Wang; Panpan Zhang; Jieqiong Li; Hui Lu; Linyi Peng; Jing Ling; Xuan Zhang; Xiaofeng Zeng; Yan Zhao; Wen Zhang

    CD4+ T cells play critical roles in the pathogenesis of IgG4-related disease (IgG4-RD). The aim of this study was to investigate the TCR repertoire of peripheral blood CD4+ T cells in IgG4-RD. The peripheral blood was collected from six healthy controls and eight IgG4-RD patients. TCR β-chain libraries of CD4+ T cells were constructed by 5′-rapid amplification of cDNA ends (5′-RACE) and sequenced by Illumina Miseq platform. The relative similarity of TCR repertoires between samples was evaluated according to the total frequencies of shared clonotypes (metric F), correlation of frequencies of shared clonotypes (metric R), and total number of shared clonotypes (metric D). The clonal expansion and diversity of CD4+ T cell repertoire were comparable between healthy controls and IgG4-RD patients, while the proportion of expanded and coding degenerated clones, as an indicator of antigen-driven clonal expansion, was significantly higher in IgG4-RD patients. There was no significant difference in TRBV and TRBJ gene usage between healthy controls and IgG4-RD patients. The complementarity determining region 3 (CDR3) length distribution was skewed towards longer fragments in IgG4-RD. Visualization of relative similarity of TCR repertoires by multi-dimensional scaling analysis showed that TCR repertoires of IgG4-RD patients were separated from that of healthy controls in F and D metrics. We identified 11 IgG4-RD-specific CDR3 amino acid sequences that were expanded in at least 2 IgG4-RD patients, while not detected in healthy controls. According to TCR clonotype networks constructed by connecting all the CDR3 sequences with a Levenshtein distance of 1, 3 IgG4-RD-specific clusters were identified. We annotated the TCR sequences with known antigen specificity according to McPAS-TCR database and found that the frequencies of TCR sequences associated with each disease or immune function were comparable between healthy controls and IgG4-RD patients. According to our study of CD4+ T cells from eight IgG4-RD patients, TCR repertoires of IgG4-RD patients were different from that of healthy controls in the proportion of expanded and coding degenerated clones and CDR3 length distribution. In addition, IgG4-RD-specific TCR sequences and clusters were identified in our study.

    更新日期:2019-12-20
  • Integrated systems analysis of salivary gland transcriptomics reveals key molecular networks in Sjögren’s syndrome
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-19
    Hong Ki Min; Su-Jin Moon; Kyung-Su Park; Ki-Jo Kim

    Treatment of patients with Sjögren’s syndrome (SjS) is a clinical challenge with high unmet needs. Gene expression profiling and integrative network-based approaches to complex disease can offer an insight on molecular characteristics in the context of clinical setting. An integrated dataset was created from salivary gland samples of 30 SjS patients. Pathway-driven enrichment profiles made by gene set enrichment analysis were categorized using hierarchical clustering. Differentially expressed genes (DEGs) were subjected to functional network analysis, where the elements of the core subnetwork were used for key driver analysis. We identified 310 upregulated DEGs, including nine known genetic risk factors and two potential biomarkers. The core subnetwork was enriched with the processes associated with B cell hyperactivity. Pathway-based subgrouping revealed two clusters with distinct molecular signatures for the relevant pathways and cell subsets. Cluster 2, with low-grade inflammation, showed a better response to rituximab therapy than cluster 1, with high-grade inflammation. Fourteen key driver genes appeared to be essential signaling mediators downstream of the B cell receptor (BCR) signaling pathway and to have a positive relationship with histopathology scores. Integrative network-based approaches provide deep insights into the modules and pathways causally related to SjS and allow identification of key targets for disease. Intervention adjusted to the molecular traits of the disease would allow the achievement of better outcomes, and the BCR signaling pathway and its leading players are promising therapeutic targets.

    更新日期:2019-12-19
  • The immune system in sporadic inclusion body myositis patients is not compromised by blood-flow restricted exercise training
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-18
    Kasper Yde Jensen; Mikkel Jacobsen; Henrik Daa Schrøder; Per Aagaard; Jakob Lindberg Nielsen; Anders Nørkær Jørgensen; Eleanor Boyle; Rune Dueholm Bech; Sofie Rosmark; Louise Pyndt Diederichsen; Ulrik Frandsen

    Sporadic inclusion body myositis (sIBM) is clinically characterised by progressive proximal and distal muscle weakness and impaired physical function while skeletal muscle tissue displays abnormal cellular infiltration of T cells, macrophages, and dendritic cells. Only limited knowledge exists about the effects of low-load blood flow restriction exercise in sIBM patients, and its effect on the immunological responses at the myocellular level remains unknown. The present study is the first to investigate the longitudinal effects of low-load blood flow restriction exercise on innate and adaptive immune markers in skeletal muscle from sIBM patients. Twenty-two biopsy-validated sIBM patients were randomised into either 12 weeks of low-load blood flow restriction exercise (BFRE) or no exercise (CON). Five patients from the control group completed 12 weeks of BFRE immediately following participation in the 12-week control period leading to an intervention group of 16 patients. Muscle biopsies were obtained from either the m. tibialis anterior or the m. vastus lateralis for evaluation of CD3-, CD8-, CD68-, CD206-, CD244- and FOXP3-positive cells by three-colour immunofluorescence microscopy and Visiopharm-based image analysis quantification. A linear mixed model was used for the statistical analysis. Myocellular infiltration of CD3−/CD8+ expressing natural killer cells increased following BFRE (P < 0.05) with no changes in CON. No changes were observed for CD3+/CD8− or CD3+/CD8+ T cells in BFRE or CON. CD3+/CD244+ T cells decreased in CON, while no changes were observed in BFRE. Pronounced infiltration of M1 pro-inflammatory (CD68+/CD206−) and M2 anti-inflammatory (CD68+/CD206+) macrophages were observed at baseline; however, no longitudinal changes in macrophage content were observed for both groups. Low-load blood flow restriction exercise elicited an upregulation in CD3−/CD8+ expressing natural killer cell content, which suggests that 12 weeks of BFRE training evokes an amplified immune response in sIBM muscle. However, the observation of no changes in macrophage or T cell infiltration in the BFRE-trained patients indicates that patients with sIBM may engage in this type of exercise with no risk of intensified inflammatory activity.

    更新日期:2019-12-19
  • Prevalence and incidence of non-gout crystal arthropathy in southern Sweden
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-17
    Mohaned Hameed; Aleksandra Turkiewicz; Martin Englund; Lennart Jacobsson; Meliha C. Kapetanovic

    To estimate the prevalence and incidence of non-gout crystal arthropathy in relation to socioeconomic factors in southern Sweden. All patients (age ≥ 18 years) with at least one visit to a physician with the diagnosis of interest in the Skåne region (population of 1.3 million) in 1998–2014 were identified. Non-gout crystal arthropathy (ICD-10 codes M11.0–M11.9) was subclassified in four different groups: calcium pyrophosphate crystal deposition related arthropathy (CPPD), unspecified non-gout arthropathies, chondrocalcinosis, and hydroxyapatite crystal deposition disease. The crude and age-adjusted point prevalence on December 31, 2014, and the cumulative incidence during 2014 were calculated for all non-gout crystal arthropathies, CPPD, and other unspecified non-gout arthropathies overall and in relation to occupation, income, and level of education. The crude 2014 point prevalence (95% CI) and 2014 cumulative incidence (95% CI) of all non-gout crystal arthropathies were 0.23% (0.23–0.24) and 21.5 (19–25) cases/100,000 persons. Mean age (range) among all prevalent cases in 2014 was 71 (20–102) years and 56% were males. The point prevalence and cumulative incidence of CPPD were 0.09% (0.08–0.09) and 8 (7–10)/100,000 persons, respectively. The corresponding data for unspecified non-gout crystal deposition disease was 0.16% (0.16–0.17) and 15.6 (13–18)/100,000 persons, respectively. The prevalence and incidence of CPPD and unspecified non-gout crystal arthropathies were slightly higher in men and increased with age irrespective of gender. Unspecified non-gout crystal arthropathy but not CPPD was less prevalent in persons with ≥ 15 years of education, whereas there were no clear associations with occupation and income. The prevalence of all diagnosed non-gout crystal arthropathies was 0.23%, thus considerably less prevalent than gout in southern Sweden. CPPD and other unspecified non-gout crystal arthropathies are the predominant diagnoses, increasing with age and in men. With the exception for unspecified non-gout crystal arthropathies being inversely correlated to a higher level of education, no convincing association with the socioeconomic factors was found.

    更新日期:2019-12-18
  • Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-17
    Scott A. Scarneo; Liesl S. Eibschutz; Phillip J. Bendele; Kelly W. Yang; Juliane Totzke; Philip Hughes; David A. Fox; Timothy A. J. Haystead

    To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 μM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). Here, we show takinib’s ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

    更新日期:2019-12-18
  • Hyaluronic acid and platelet-rich plasma, a new therapeutic alternative for scleroderma patients: a prospective open-label study
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-13
    Roberto Pirrello; Barbara Verro; Giulia Grasso; Piero Ruscitti; Adriana Cordova; Roberto Giacomelli; Francesco Ciccia; Giuliana Guggino

    Systemic sclerosis is a systemic connective tissue disease characterized by endothelium damage, fibrosis, and subsequent atrophy of the skin. Perioral fibrosis produces a characteristic microstomia together with microcheilia, both of which cause severe difficulties and affects patients’ daily life, such as eating and oral hygiene. Since there are no effective and specific therapies, we have aimed at evaluating the response to filler injections of hyaluronic acid together with platelet-rich plasma. Ten female patients aged between 18 and 70 were included in this study. Each patient was treated with three filler injections of hyaluronic acid and platelet-rich plasma at an interval of 15 to 20 days. Follow-up check-ups were recorded 1, 3, and 24 months after the end of the treatment. During the therapy and the subsequent follow-up, we evaluated the mouth’s opening, freedom of movement of the lips, and skin elasticity. After the treatment, patients had achieved good results already after the first injection and the improvement was maintained in the following months, up to 2 years. In particular, 8 (80%) patients showed a greater mouth’s opening and increased upper lip’s thickness during 1-month follow-up and maintained these results after 2 years (maximum mouth’s opening T0 47.61; T3 49.23; T4 48.60 p < 0.0001. Upper lip’s thickness T0 4.20; T3 4.75; T4 4.45 p < 0.0001). Moreover, distance between upper and lower incisors (T0 27.05; T3 29.03; T4 28.14 p < 0.0001), inter-commissural distance (T0 49.12; T3 51.44; T4 50.31: p < 0.0001), and lower lip’s thickness (T0 3.80; T3 4.85, 5.10; T4 4.25; p < 0.0001) were increased in all of patients in 1-month follow-up, keeping these benefits after 24 months and having a significant increase of skin elasticity 1 month after the end of therapy. Our study demonstrates that filler injections of hyaluronic acid and platelet-rich plasma represent an efficient local therapeutic alternative for patients affected by scleroderma. The treatment has significantly improved patients’ quality of living.

    更新日期:2019-12-17
  • Performance of cytokine models in predicting SLE activity
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-16
    Nopparat Ruchakorn; Pintip Ngamjanyaporn; Thanitta Suangtamai; Thanuchporn Kafaksom; Charin Polpanumas; Veerachat Petpisit; Trairak Pisitkun; Prapaporn Pisitkun

    Identification of universal biomarkers to predict systemic lupus erythematosus (SLE) flares is challenging due to the heterogeneity of the disease. Several biomarkers have been reported. However, the data of validated biomarkers to use as a predictor for lupus flares show variation. This study aimed to identify the biomarkers that are sensitive and specific to predict lupus flares. One hundred and twenty-four SLE patients enrolled in this study and were prospectively followed up. The evaluation of disease activity achieved by the SLE disease activity index (SLEDAI-2K) and clinical SLEDAI (modified SLEDAI). Patients with active SLE were categorized into renal or non-renal flares. Serum cytokines were measured by multiplex bead-based flow cytometry. The correlation and logistic regression analysis were performed. Levels of IFN-α, MCP-1, IL-6, IL-8, and IL-18 significantly increased in active SLE and correlated with clinical SLEDAI. Complement C3 showed a weakly negative relationship with IFN-α and IL-18. IL-18 showed the highest positive likelihood ratios for active SLE. Multiple logistic regression analysis showed that IL-6, IL-8, and IL-18 significantly increased odds ratio (OR) for active SLE at baseline while complement C3 and IL-18 increased OR for active SLE at 12 weeks. IL-18 and IL-6 yielded higher sensitivity and specificity than anti-dsDNA and C3 to predict active renal and active non-renal, respectively. The heterogeneity of SLE pathogenesis leads to different signaling mechanisms and mediates through several cytokines. The monitoring of cytokines increases the sensitivity and specificity to determine SLE disease activity. IL-18 predicts the risk of active renal SLE while IL-6 and IL-8 predict the risk of active non-renal. The sensitivity and specificity of these cytokines are higher than the anti-dsDNA or C3. We propose to use the serum level of IL-18, IL-6, and IL-8 to monitor SLE disease activity in clinical practice.

    更新日期:2019-12-17
  • Protein profiling and network enrichment analysis in individuals before and after the onset of rheumatoid arthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-16
    Mikael Brink; Anders Lundquist; Andrey Alexeyenko; Kristina Lejon; Solbritt Rantapää-Dahlqvist

    Antibodies and upregulated cytokines and chemokines predate the onset of rheumatoid arthritis (RA) symptoms. We aimed to identify the pathways related to the early processes leading to RA development, as well as potential novel biomarkers, using multiple protein analyses. A case-control study was conducted within the Biobank of northern Sweden. The plasma samples from 118 pre-symptomatic individuals (207 samples; median predating time 4.1 years), 79 early RA patients, and 74 matched controls were analyzed. The levels of 122 unique proteins with an acknowledged relationship to autoimmunity were analyzed using 153 antibodies and a bead-based multiplex system (FlexMap3D; Luminex Corp.). The data were analyzed using multifactorial linear regression model, random forest, and network enrichment analysis (NEA) based on the 10 most significantly differentially expressed proteins for each two-by-two group comparison, using the MSigDB collection of hallmarks. There was a high agreement between the different statistical methods to identify the most significant proteins. The adipogenesis and interferon alpha response hallmarks differentiated pre-symptomatic individuals from controls. These two hallmarks included proteins involved in innate immunity. Between pre-symptomatic individuals and RA patients, three hallmarks were identified as follows: apical junction, epithelial mesenchymal transition, and TGF-β signaling, including proteins suggestive of cell interaction, remodulation, and fibrosis. The adipogenesis and heme metabolism hallmarks differentiated RA patients from controls. We confirm the importance of interferon alpha signaling and lipids in the early phases of RA development. Network enrichment analysis provides a tool for a deeper understanding of molecules involved at different phases of the disease progression.

    更新日期:2019-12-17
  • The burden of metabolic syndrome on osteoarthritic joints
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-16
    Bruce M. Dickson; Anke J. Roelofs; Justin J. Rochford; Heather M. Wilson; Cosimo De Bari

    The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes. A skewing of macrophages towards a pro-inflammatory M1 phenotype within synovial and adipose tissues is thought to play a role in OA pathogenesis. The metabolic perturbations typical of MetS are important drivers of pro-inflammatory macrophage polarisation and activity. This is mediated via alterations in the levels and activities of the cellular nutrient sensors 5′ adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1), intracellular accumulation of metabolic intermediates such as succinate and citrate, and increases in free fatty acids (FFAs) and hyperglycaemia-induced advanced glycation end-products (AGEs) that bind to receptors on the macrophage surface. Altered levels of adipokines, including leptin and adiponectin, further influence macrophage polarisation. The metabolic alterations in MetS also affect the cartilage through direct effects on chondrocytes by stimulating the production of pro-inflammatory and catabolic factors and possibly by suppressing autophagy and promoting cellular senescence. The influence of MetS on OA pathogenesis involves a wide range of metabolic alterations that directly affect macrophages and chondrocytes. The relative burden of intra-articular versus systemic adipose tissue in the MetS-associated OA remains to be clarified. Understanding how altered metabolism interacts with joints affected by OA is crucial for the development of further strategies for treating this debilitating condition, such as supplementing existing therapies with metformin and utilising ω-3 fatty acid derivatives to restore imbalances in ω-3 and ω-6 fatty acids.

    更新日期:2019-12-17
  • DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-16
    Zongwang Zhang; Yanwei Wu; Bing Wu; Qing Qi; Heng Li; Huimin Lu; Chen Fan; Chunlan Feng; Jianping Zuo; Lili Niu; Wei Tang

    Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models. The anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated. DZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor β1, connective tissue growth factor, tumor necrosis factor-α, interferon-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-β1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-β/Smad signaling pathway. DZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.

    更新日期:2019-12-17
  • FKB327, an adalimumab biosimilar, versus the reference product: results of a randomized, Phase III, double-blind study, and its open-label extension
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-12
    Mark C. Genovese; Josephine Glover; Maria Greenwald; Wieslawa Porawska; Elias Chalouhi El Khouri; Eva Dokoupilova; Juan Ignacio Vargas; Mykola Stanislavchuk; Herbert Kellner; Elena Baranova; Nobuhito Matsunaga; Rieke Alten

    To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA). Patients were randomized 1:1 in a double-blind study (NCT02260791), received 40 mg of FKB327 or RP by subcutaneous injection every other week for 24 weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ± 13% and − 12% to + 15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54. A total of 730 patients were randomized in Period I (n = 367 FKB327, n = 363 RP), and 645 transitioned to Period II (n = 216 FKB327–FKB327, n = 108 FKB327–RP, n = 108 RP–FKB327, n = 213 RP–RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were − 7.9 to 4.7% and − 7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II. FKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed. ClinicalTrials.gov, NCT02260791, Registered 29 July 2014. ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.

    更新日期:2019-12-13
  • Is 18F-FDG PET/CT useful for diagnosing relapsing polychondritis with airway involvement and monitoring response to steroid-based therapy?
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-12
    Yunxiang Zeng; Minfang Li; Sheng Chen; Lin Lin; Shiyue Li; Jianxing He; Jinlin Wang

    18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is a promising tool for diagnosing relapsing polychondritis (RP). However, its usefulness in assessing RP with airway involvement is unknown. This study aimed to further evaluate and confirm the potency of 18F-FDG PET/CT in diagnosing RP with airway involvement and monitoring response to steroid-based therapy. A total of 30 patients from a dedicated respiratory centre, diagnosed with RP in accordance with McAdam, Damiani or Levine criteria, were included in this study. All patients underwent baseline 18F-FDG PET/CT, and 10 patients underwent second scans after 2.5–15 months of steroid-based therapy. Visual scores (VS) and maximal standard uptake values (SUVmax) were analysed. In the initial scan, 83.3% (25/30) of patients were found to have FDG uptake in more than one cartilage. The median VS and SUVmax in the cartilages were 3 (range, 1–3) and 3.8 (range, 1.9–17.9), respectively. Positive rates for PET/CT-guided biopsy in nasal, auricular, and tracheal/bronchial cartilages were 100% (5/5), 88.9% (8/9), and 10.5% (2/19), respectively, but the positive biopsy rate in the auricular cartilage was 92.3% (12/13) even without PET/CT assessment. Based on biopsy-proven sites, the sensitivity of PET/CT was 55.6%, and the specificity was 5.3%. Compared with the baseline scan, the second scan showed much lower median VS (2 vs 3, respectively; p < 0.0001) and SUVmax (2.9 vs 3.8, respectively; p < 0.001). Of 10 patients who underwent second PET/CT, 8 had complete therapeutic response, while 2 had partial response. 18F-FDG PET/CT assists in identifying multiple cartilage involvement in RP, but it seems neither a sensitive nor specific modality in diagnosing RP with airway involvement. Moreover, PET/CT has limited utility in locating biopsy sites and monitoring therapeutic response to corticosteroids.

    更新日期:2019-12-13
  • Promotion of osteoclastogenesis by IL-26 in rheumatoid arthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-12
    Kyung-Ann Lee; Kyoung-Woon Kim; Bo-Mi Kim; Ji-Yeon Won; Hong Ki Min; Dhong Won Lee; Hae-Rim Kim; Sang-Heon Lee

    The inflammatory cascade in the rheumatoid arthritis (RA) synovium is modulated by a variety of cytokine and chemokine networks; however, the roles of IL-26, in RA pathogenesis, are poorly defined. Here, we investigated the functional role of interleukin-26 (IL)-26 in osteoclastogenesis in RA. We analyzed levels of IL-20 receptor subunit A (IL-20RA), CD55, and receptor activator of nuclear factor kappaB (NF-κB) ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs) using confocal microscopy. Recombinant human IL-26-induced RANKL expression in RA-FLSs was examined using real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured with macrophage colony-stimulating factor (M-CSF) and IL-26, after which osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase-positive multinucleated cells. Additionally, osteoclastogenesis was evaluated by monocytes co-cultured with IL-26-prestimulated FLSs. The expression of IL-20RA in RA-FLSs was higher than that in osteoarthritis-FLSs. Additionally, in IL-26-pretreated RA-FLSs, the expression of IL-20RA (but not IL-10 receptor subunit B) and RANKL increased in a dose-dependent manner, with IL-26-induced RANKL expression reduced by IL-20RA knockdown. Moreover, IL-26-induced RANKL expression was significantly downregulated by inhibition of signal transducer and activator of transcription 1, mitogen-activated protein kinase, and NF-κB signaling. Furthermore, IL-26 promoted osteoclast differentiation from peripheral blood monocytes in the presence of low dose of RANKL, with IL-26 exerting an additive effect. Furthermore, co-culture of IL-26-pretreated RA-FLSs with peripheral blood monocytes also increased osteoclast differentiation in the absence of addition of RANKL. IL-26 regulated osteoclastogenesis in RA through increased RANKL expression in FLSs and direct stimulation of osteoclast differentiation. These results suggest the IL-26/IL-20RA/RANKL axis as a potential therapeutic target for addressing RA-related joint damage.

    更新日期:2019-12-13
  • Alterations of voluntary behavior in the course of disease progress and pharmacotherapy in mice with collagen-induced arthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-12
    Yohsuke Oto; Yukari Takahashi; Daitaro Kurosaka; Fusao Kato

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis and bone destruction at the joints, causing pain and motor disturbance. Despite the better control of inflammation and joint deformity afforded by modern disease-modifying anti-rheumatic drugs, many patients with RA remain dissatisfied with their treatment, primarily because of sensory-emotional distress. Pre-clinical tests that can evaluate not only the symptoms of arthritis but also the associated pain as sensory-emotional experience are urgently needed. Here, we introduce two types of novel methods for evaluation of voluntary behavior in a commonly used model of RA (collagen-induced arthritis; CIA) in male mice. First, spontaneous motor activity was assessed with a running wheel placed in home cages and the number of rotations was continuously recorded in a 12:12-h light environment. Second, temperature preference was assessed by measuring the time spent in either of the floor plates with augmenting (25 to 49 °C) or fixed temperature (25 °C). We also evaluated the effects of tofacitinib on CIA-associated changes in voluntary wheel running and temperature preference. We detected a significant decrease in voluntary wheel running, a significant shift in the distribution of movement in the dark phase, and a significant increase in the time spent in warmer environments than the room temperature in the mice with CIA. These alterations in voluntary behavior have never been described with conventional methods. We also revealed tofacitinib-resistant significant changes in the voluntary behavior and choice of temperature despite significant mitigation of the symptoms of arthritis. We described for the first time significant alterations of the voluntary behavior of the mice with CIA during the clinical periods, indicating that the overall physical/motivational states and its circadian variation, as well as the specific preference to a certain environmental temperature, are modified in the mice with CIA, as observed in human patients. Some of these did not parallel with the conventional arthritis scores, particularly during the pharmacotherapy suggesting that mice with CIA show not only the peripheral symptoms but also the central consequences. The use of these approaches would also help clarify the biological mechanisms underlying physician-patient discordance in the assessment of RA.

    更新日期:2019-12-13
  • Will savings from biosimilars offset increased costs related to dose escalation? A comparison of infliximab and golimumab for rheumatoid arthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-12
    Jeffrey R. Curtis; Fenglong Xie; Jonathan Kay; Joel D Kallich

    Biosimilar infliximab has the potential for appreciable cost savings compared to its reference biologic, but dose escalation is common and increases costs. We compared frequency of dose escalation and associated Medicare-approved amount so as to determine the break-even point at which infliximab dose escalation would offset the cost savings of using a biosimilar, referent to alternatively using golimumab. We studied Medicare enrollees with rheumatoid arthritis (RA) initiating infliximab or golimumab. Frequency of dose escalation was summarized descriptively over 18 months, as were Medicare-approved amounts for reimbursement. Analyses were repeated conditioning on high adherence (i.e., non-discontinuation, > 10-week gap). Multivariable-adjusted logistic regression and mixed models evaluated factors associated with infliximab dose escalation. A total of 5174 infliximab and 2843 golimumab initiators were observed. Dose escalation was rare for golimumab (5%) but common for infliximab (49%), and was even more common (72%) for infliximab among patients who persisted on treatment. Regardless of dose escalation, the adjusted least square mean dollar amounts were appreciably higher for golimumab ($28,146) than for infliximab ($21,216) and greater among persistent patients (cost difference $9269, favoring infliximab). Only when patients escalated infliximab to ≥ 8 mg/kg every 6 weeks was golimumab IV at break-even or less expensive. After controlling for multiple factors, physician ownership of the infusion center was associated with greater likelihood of infliximab dose escalation (odds ratio = 1.25, 95% CI 1.09–1.44). Despite frequent dose escalation with infliximab that often increase its dose by threefold or more, the savings from the current price of its biosimilar substantially offsets the costs of an alternative infused TNFi biologic for which no biosimilar is available.

    更新日期:2019-12-13
  • Management of adult-onset Still’s disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-11
    Serena Colafrancesco; Maria Manara; Alessandra Bortoluzzi; Teodora Serban; Gerolamo Bianchi; Luca Cantarini; Francesco Ciccia; Lorenzo Dagna; Marcello Govoni; Carlomaurizio Montecucco; Roberta Priori; Angelo Ravelli; Paolo Sfriso; Luigi Sinigaglia

    Adult-onset Still’s disease (AOSD) is a rare inflammatory condition characterized by fever, rash, and arthritis. Because of its rarity, clinical trials are inherently small and often uncontrolled. Our objective was to develop recommendations for the use of interleukin (IL)-1 inhibitors in the management of patients with AOSD, based on the best evidence and expert opinion. A panel of 10 experts (9 rheumatologists and 1 pediatrician) was established. The first step was dedicated to a comprehensive literature review and development of statements. Two separate literature searches were performed on the MEDLINE (Pubmed), EMBASE, and BIOSIS databases through April 2018 to identify (1) differences and similarities between AOSD and pediatric Still’s disease (systemic juvenile idiopathic arthritis [SJIA]) and (2) the efficacy and safety of IL-1 inhibitors in AOSD treatment. In the second step, the statements were submitted in a Delphi process to a panel of 67 rheumatologists. Consensus threshold was set at 66%: positive, > 66% of voters selected scores 3 to 5; negative, > 66% of voters selected scores 1 or 2. In the third step, the voting results were analyzed, and the statements were finalized. Eleven statements were developed. Forty-six of 67 rheumatologists (72%) participated in the Delphi process. A positive consensus was reached after the first round of voting and was full (> 95%) on the majority of statements. A large consensus was achieved in considering AOSD and SJIA as the same disease. The use of anti-IL-1 therapies in refractory patients was considered quite safe and effective both as the first and as a subsequent line of biologic treatment, especially in systemic patients. Because of the lack of head-to-head comparisons, a different profile of efficacy among IL-1 inhibitors could not be established. There was a large consensus that failure of the first IL-1 inhibitor does not preclude response to another one. The lack of studies comparing early versus late treatment did not allow to draw conclusions; however, data from SJIA suggest a better response in early treatment. The Delphi method was used to develop recommendations that we hope will help clinicians in the management of patients with AOSD refractory to conventional therapies.

    更新日期:2019-12-11
  • LNA-anti-miR-150 ameliorated kidney injury of lupus nephritis by inhibiting renal fibrosis and macrophage infiltration
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-11
    Junjun Luan; Jingqi Fu; Chengjie Chen; Congcong Jiao; Weiwei Kong; Yixiao Zhang; Qing Chang; Yanqiu Wang; Detian Li; Gabor G. Illei; Jeffrey B. Kopp; Jingbo Pi; Hua Zhou

    The prevalence of lupus nephritis (LN) remains high despite various emerging monoclonal antibodies against with targeting systemic lupus erythematosus (SLE). Renal fibrosis is the main feature of late stage LN, and novel therapeutic agents are still needed. We previously reported that microRNA (miR)-150 increases in renal biopsies of American LN patients and that miR-150 agonist promotes fibrosis in cultured kidney cells. Presently, we aim to verify whether locked nucleic acid (LNA)-anti-miR-150 can ameliorate LN in mice and to investigate its corresponding mechanisms. We first observed natural history and renal miR-150 expression in female Fcgr2b−/− mice of a spontaneously developed LN model. We then verified miR-150 renal absorption and determined the dose of the suppressed miR-150 by subcutaneous injection of LNA-anti-miR-150 (2 and 4 mg/kg). Thirdly, we investigated the therapeutic effects of LNA-anti-miR-150 (2 mg/kg for 8 weeks) on LN mice and the corresponding mechanisms by studying fibrosis-related genes, cytokines, and kidney resident macrophages. Lastly, we detected the expression of renal miR-150 and the mechanism-associated factors in renal biopsies from new onset untreated LN patients. Fcgr2b−/− mice developed SLE indicated by positive serum autoantibodies at age 19 weeks and LN demonstrated by proteinuria at age 32 weeks. Renal miR-150 was overexpressed in LN mice compared to wild type mice. FAM-labeled LNA-anti-miR-150 was absorbed by both glomeruli and renal tubules. LNA-anti-miR-150 suppressed the elevated renal miR-150 levels in LN mice compared to the scrambled LNA without systemic toxicity. Meanwhile, serum double strand-DNA antibody, proteinuria, and kidney injury were ameliorated. Importantly, the elevated renal pro-fibrotic genes (transforming growth factor-β1, α-smooth muscle antibody, and fibronectin) and decreased anti-fibrotic gene suppressor of cytokine signal 1 were both reversed. Renal pro-inflammatory cytokines (interferon-γ, interleukin-6, and tumor necrosis factor-α) and macrophages were also decreased. In addition, the changes of renal miR-150 and associated proteins shown in LN mice were also seen in human subjects. LNA-anti-miR-150 may be a promising novel therapeutic agent for LN in addition to the current emerging monoclonal antibodies, and its renal protective mechanism may be mediated by anti-fibrosis and anti-inflammation as well as reduction of the infiltrated kidney resident macrophages.

    更新日期:2019-12-11
  • Activation of natural killer cells by rituximab in granulomatosis with polyangiitis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-11
    Doris Urlaub; Shuyang Zhao; Norbert Blank; Raoul Bergner; Maren Claus; Theresa Tretter; Hanns-Martin Lorenz; Carsten Watzl; Wolfgang Merkt

    In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab’s mechanism of action in GPA. B cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry. NK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions. B cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab’s mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.

    更新日期:2019-12-11
  • Proposition of a novel animal model of systemic sclerosis induced by type V collagen in C57BL/6 mice that reproduces fibrosis, vasculopathy and autoimmunity
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-11
    Walcy Rosolia Teodoro; Zelita Aparecida de Jesus Queiroz; Lais Araujo dos Santos; Sergio Catanozi; Antonio dos Santos Filho; Cleonice Bueno; Margarete B. G. Vendramini; Sandra de Morais Fernezlian; Esmeralda M. Eher; Percival D. Sampaio-Barros; Sandra Gofinet Pasoto; Fernanda Degobbi T. Q. S. Lopes; Ana Paula Pereira Velosa; Vera Luiza Capelozzi

    Type V collagen (Col V) has the potential to become an autoantigen and has been associated with the pathogenesis of systemic sclerosis (SSc). We characterized serological, functional, and histopathological features of the skin and lung in a novel SSc murine model induced by Col V immunization. Female C57BL/6 mice (n = 19, IMU-COLV) were subcutaneously immunized with two doses of Col V (125 μg) emulsified in complete Freund adjuvant, followed by two intramuscular boosters. The control group (n = 19) did not receive Col V. After 120 days, we examined the respiratory mechanics, serum autoantibodies, and vascular manifestations of the mice. The skin and lung inflammatory processes and the collagen gene/protein expressions were analyzed. Vascular manifestations were characterized by endothelial cell activity and apoptosis, as shown by the increased expression of VEGF, endothelin-1, and caspase-3 in endothelial cells. The IMU-COLV mice presented with increased tissue elastance and a nonspecific interstitial pneumonia (NSIP) histologic pattern in the lung, combined with the thickening of the small and medium intrapulmonary arteries, increased Col V fibers, and increased COL1A1, COL1A2, COL3A1, COL5A1, and COL5A2 gene expression. The skin of the IMU-COLV mice showed thickness, epidermal rectification, decreased papillary dermis, atrophied appendages, and increased collagen, COL5A1, and COL5A2 gene expression. Anti-collagen III and IV and ANA antibodies were detected in the sera of the IMU-COLV mice. We demonstrated that cutaneous, vascular, and pulmonary remodeling are mimicked in the Col V-induced SSc mouse model, which thus represents a suitable preclinical model to study the mechanisms and therapeutic approaches for SSc.

    更新日期:2019-12-11
  • The value of MRI examination on bilateral hands including proximal interphalangeal joints for disease assessment in patients with early rheumatoid arthritis: a cross-sectional cohort study
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-11
    Ying-Qian Mo; Ze-Hong Yang; Jun-Wei Wang; Qian-Hua Li; Xin-Yun Du; T. W. Huizinga; X. M. E. Matthijssen; Guang-Zi Shi; Jun Shen; Lie Dai

    Bilateral hands including proximal interphalangeal joints (PIPJs) are recommended on physical, X-ray radiographic, or ultrasonographic examination by clinical guidelines of rheumatoid arthritis (RA), but MRI still tends to examine unilateral wrists and/or MCPJs. We aimed to demonstrate the advantages of MRI examination on bilateral hands including PIPJs for disease assessment in early RA patients. Active early RA patients received 3.0T whole-body MRI examination with contrast-enhanced imaging on bilateral wrists, MCPJs, and PIPJs. MRI features were scored referring to the updated RAMRIS. Clinical assessments were conducted on the day of MRI examination. The mean time of MRI examination was 24 ± 3 min. MRI bone erosion in MCPJs would be missed-diagnosed in 23% of patients if non-dominant MCPJs were scanned unilaterally, while osteitis in MCPJs would be missed-diagnosed in 16% of patients if dominant MCPJs were scanned unilaterally. MRI synovitis severity was also asymmetric: 21% of patients showing severe synovitis unilaterally in non-dominant MCPJs/PIPJs and other 20% showing severe synovitis unilaterally in dominant MCPJs/PIPJs. Among these early RA patients, MRI tenosynovitis occurred the most frequently in wrist extensor compartment I, while MRI examination on bilateral hands demonstrated no overuse influence present. However, overuse should be considered in dominant PIPJ2, PIPJ4, and IPJ of thumb of which MRI tenosynovitis prevalence was respectively 18%, 17%, or 16% higher than the non-dominant counterparts. Early MRI abnormality of nervus medianus secondary to severe tenosynovitis occurred either in dominant or non-dominant wrists; MRI of unilateral hands would take a risk of missed-diagnosis. Common MRI findings in PIPJs were synovitis and tenosynovitis, respectively in 87% and 69% of patients. MRI tenosynovitis prevalence in IPJ of thumb or PIPJ5 was much higher than the continued wrist flexor compartments. MRI synovitis or tenosynovitis in PIPJs independently increased more than twice probability of joint tenderness (OR = 2.09 or 2.83, both p < 0.001). In consideration of asymmetric MRI features in early RA, potential overuse influence for certain tenosynovitis in dominant hands, and high prevalence of MRI findings in PIPJs, MRI examination on bilateral hands including PIPJs is deserved for disease assessment in early RA patients.

    更新日期:2019-12-11
  • Improved RA classification among early arthritis patients with the concordant presence of three RA autoantibodies: analysis in two early arthritis clinics
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-11
    Cristina Regueiro; Lorena Rodríguez-Martínez; Laura Nuño; Ana M. Ortiz; Alejandro Villalba; Dora Pascual-Salcedo; Ana Martínez-Feito; Isidoro González-Alvaro; Alejandro Balsa; Antonio Gonzalez

    The patients with RA benefit from early identification soon after the first clinical symptoms appear. The 2010 ACR/EULAR classification criteria were developed to fulfill this need and their application has been demonstrated to be effective. However, there is still room for improvement. Therefore, we aimed to evaluate the potential of the concordant presence of RF, anti-CCP and anti-carbamylated protein antibodies to improve current RA classification among early arthritis (EA) patients. Data from the first visit of 1057 patients in two EA prospective cohorts were used. The serological scores from the 2010 ACR/EULAR criteria and the concordant presence of the three RA autoantibodies were assessed relative to a gold standard consisting of the RA classification with the 1987 ACR criteria at the 2 years of follow-up. The concordant presence of three antibodies showed predictive characteristics allowing for direct classification as RA (positive predictive value = 96.1% and OR = 80.9). They were significantly better than the corresponding to the high antibody titers defined as in the 2010 classification criteria (PPV = 88.8%, OR = 26.1). In addition, the concordant presence of two antibodies was also very informative (PPV = 82.3%, OR = 15.1). These results allowed devising a scoring system based only on antibody concordance that displayed similar overall performance as the serological scoring system of the 2010 criteria. However, the best classification was obtained combining the concordance and 2010 serological systems, a combination with a significant contribution from each of the two systems. The concordant presence of RA autoantibodies showed an independent contribution to the classification of EA patients that permitted increased discrimination and precision.

    更新日期:2019-12-11
  • Long non-coding XIST raises methylation of TIMP-3 promoter to regulate collagen degradation in osteoarthritic chondrocytes after tibial plateau fracture
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-09
    Hongwei Chen; Shengdi Yang; Ruyi Shao

    Hypermethylation of gene promoters has been regarded as an epigenetic regulator for gene inactivation in the development of several diseases. In the current study, we aimed to explore how long noncoding RNA X-inactive specific transcript (lncRNA XIST) function in collagen degradation in chondrocytes of osteoarthritis (OA) after tibial plateau fracture by regulating tissue inhibitor of metalloproteinase-3 (TIMP-3) promoter methylation. In silico analysis was used to screen differentially expressed lncRNAs in cartilage tissues of OA. Chondrocytes were then successfully isolated from normal and OA cartilage tissues and identified, with the expressions of lncRNA XIST and TIMP-3 examined. The methylation levels of TIMP-3 promoter were determined by MS-PCR. The binding of lncRNA XIST to DNA methyltransferase and the binding of TIMP-3 promoter to DNA methyltransferase were determined by a series of experiments, including RIP, RNA pull-down, and ChIP assays. The differentially expressed lncRNA XIST was determined in OA. In addition, cartilage tissues of OA showed upregulation of lncRNA XIST and downregulation of TIMP-3. LncRNA XIST was primarily localized in the nucleus and was capable of binding to the promoter of TIMP-3. The silencing of lncRNA XIST decreased the methylation levels of TIMP-3 promoter and increased the expressions of TIMP-3, which consequently inhibited collagen degradation in OA chondrocytes. Furthermore, TIMP-3 over-expression reversed the effect of lncRNA XIST on collagen degradation in OA chondrocytes. Collectively, lncRNA XIST raises collagen degradation in OA chondrocytes after tibial plateau fracture by accelerating the methylation of TIMP-3 promoter by recruiting DNA methyltransferase.

    更新日期:2019-12-11
  • Upadacitinib improves patient-reported outcomes in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying antirheumatic drugs: results from SELECT-NEXT
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-09
    Vibeke Strand; Janet Pope; Namita Tundia; Alan Friedman; Heidi S. Camp; Aileen Pangan; Arijit Ganguli; Mahesh Fuldeore; Debbie Goldschmidt; Michael Schiff

    To evaluate the effect of upadacitinib on patient-reported outcomes (PROs) in patients with RA who had an inadequate response to csDMARDs. Patients in SELECT-NEXT, a randomised controlled trial, were on a background of csDMARDs and received upadacitinib 15 mg and 30 mg or placebo daily for 12 weeks. PROs included Patient Global Assessment of Disease Activity (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration and severity of morning (AM) joint stiffness, Short Form 36 Health Survey (SF-36), and Work Instability Scale for RA (RA-WIS). Least squares mean (LSM) changes were based on mixed-effect repeated measure models. Percentages of patients reporting improvements ≥ minimum clinically important differences (MCIDs) and scores ≥ normative values and number needed to treat (NNT) were determined; group comparisons used chi-square tests. Data from 661 patients were analysed. Compared with placebo, patients receiving upadacitinib reported statistically significant improvements (both doses, P < 0.05) in PtGA, pain, HAQ-DI, FACIT-F, duration and severity of AM stiffness, SF-36 (PCS and 6/8 domains), and RA-WIS at week 12. Significantly, more upadacitinib-treated patients (both doses, P < 0.05) reported improvements ≥ MCID in PtGA, pain, HAQ-DI, FACIT-F, AM stiffness, SF-36 (PCS and 4 or 7/8 domains), and RA-WIS and scores ≥ normative values in HAQ-DI, FACIT-F, and SF-36 (PCS and 4 or 5/8 domains). For most PROs, the incremental NNT with upadacitinib to report clinically meaningful improvement from baseline ranged from 4 to 8 patients. Upadacitinib 15 mg or 30 mg daily for 12 weeks resulted in significant and clinically meaningful improvements in global disease activity, pain, physical function, fatigue, duration and severity of AM stiffness, HRQOL, and work instability among csDMARD-IR patients with RA. Clinicaltrials.gov, NCT02675426. Retrospectively registered 5 February 2016.

    更新日期:2019-12-11
  • Association of age, sex and BMI with the rate of change in tibial cartilage volume: a 10.7-year longitudinal cohort study
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-09
    Guoqi Cai; Matthew Jiang; Flavia Cicuttini; Graeme Jones

    To describe the association of age, sex and body mass index with the rate of change of tibial knee cartilage volume over 10.7 years in a community-based sample of older adults. Four hundred and eighty-one participants (49% female, mean age 60.8 years [range 51.1–79.7], 49% had knee pain and 58% radiographic osteoarthritis) were included. Tibial cartilage volume of the right knee was assessed on T1-weighted fat-suppressed 1.5 T MRI at baseline and 10.7 years. Data analyses were performed using linear regression models. The average rate of loss of cartilage volume was 1.2%/year (range 0.2–3.9%) with all participants losing cartilage volume over the study period. There was a significant association between age and loss of tibial cartilage volume in the medial (0.023%/year, 95% confidence interval [CI] 0.010 to 0.036%, p < 0.001), lateral (0.013%/year, 95% CI 0.003 to 0.023%, p = 0.012) and total tibia (0.018%/year, 95% CI 0.009 to 0.026%, p < 0.001). Higher body mass index at baseline and increases in body mass index over time were associated with a greater tibial cartilage loss at the medial (body mass index at baseline 0.040%/year, 95% CI 0.022 to 0.058%, p < 0.001; increases in body mass index 0.055%/year, 95% CI 0.018 to 0.093%, p = 0.004) but not lateral compartment. No evidence of non-linear relationships was observed. Compared to males, females lost more lateral tibial cartilage with increasing age (0.023%/year, 95% CI 0.003 to 0.043%, p = 0.024 for interaction). Tibial cartilage volume declines at a faster rate with increasing age and body mass index in both males and females, particularly in the medial compartment. In contrast to the low rate of change in radiographs, our findings suggest that cartilage loss at the tibia is universal in this age group.

    更新日期:2019-12-11
  • Complex assessment of bone mineral density, fracture risk, vitamin D status, and bone metabolism in Hungarian systemic sclerosis patients
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-10
    Ágnes Horváth; Edit Végh; Anita Pusztai; Zsófia Pethő; Attila Hamar; Monika Czókolyová; Harjit Pal Bhattoa; Gábor Nagy; Balázs Juhász; Katalin Hodosi; Andrea Domján; Zoltán Szekanecz; Gabriella Szücs; Szilvia Szamosi

    We wished to determine bone alterations in systemic sclerosis (SSc) patients by conventional densitometry (DXA), peripheral quantitative computed tomography (pQCT), and bone biomarkers. We included 44 SSc patients and 33 age-matched healthy controls. Lumbar spine and femoral neck bone mineral density (BMD) was assessed by DXA. Volumetric BMD was measured by pQCT at the radius. FRAX, 25-hydroxyvitamin-D3 (25-OH-D3), parathyroid hormone, osteocalcin, C-terminal collagen telopeptide, and procollagen type I amino-terminal propeptide were also assessed. SSc patients had lower L2–4 BMD (0.880 ± 0.108 vs. 0.996 ± 0.181 g/cm2; p = 0.019) and femoral neck (FN) BMD (0.786 ± 0.134 vs. 0.910 ± 0.090 g/cm2; p = 0.007) by DXA. In SSc vs. controls, pQCT indicated lower mean cortical (328.03 ± 103.32 vs. 487.06 ± 42.45 mg/cm3; p < 0.001) and trabecular density (150.93 ± 61.91 vs. 184.76 ± 33.03 mg/cm3; p = 0.037). Vitamin D3 deficiency was more common in SSc vs. controls (60.0% vs. 39.3%; p = 0.003). L2–4 (p = 0.002) and FN BMD (p = 0.015) positively correlated with BMI. pQCT assessments confirmed an inverse correlation between pulmonary manifestation and total (p = 0.024), trabecular (p = 0.035), and cortical density (p = 0.015). Anti-Scl70 positivity inversely correlated with pQCT total density (p = 0.015) and the presence of digital ulcers with cortical density (p = 0.001). We also found that vertebral and FN BMD as determined by DXA significantly correlated with pQCT total, trabecular, and cortical density (p < 0.05). The results of our study suggest that bone loss in SSc patients may be associated with lower BMI, anti-Scl70 positivity, and the presence of pulmonary manifestations and digital ulcers. Both DXA and pQCT are appropriate tools to evaluate the bone alterations in SSc patients.

    更新日期:2019-12-11
  • Progressive structural bone changes and their relationship with treatment in patients with psoriatic arthritis: a longitudinal HR-pQCT study
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-04
    Dongze Wu; James F. Griffith; Steven H. M. Lam; Priscilla C. H. Wong; Lin Shi; Edmund K. Li; Isaac T. Cheng; Tena K. Li; Vivian W. Hung; Ling Qin; Lai-Shan Tam

    Although the short-term effects of tumor necrosis factor alpha (TNF-α) and interleukin-17A (IL-17A) inhibition on the structural changes in psoriatic arthritis (PsA) using high-resolution peripheral quantitative computed tomography (HR-pQCT) have been reported, no studies have investigated the long-term structural changes in PsA patients receiving routine care. We reported longitudinal changes of erosions and enthesiophytes using HR-pQCT and their relationship with treatments in PsA patients over a 5-year period. HR-pQCT examination at the second and third metacarpal heads (MCH2 and MCH3) was performed in 60 PsA patients at baseline and after 5 years. The size of each individual lesion was quantified. Erosion and enthesiophyte progression were defined as change exceeding the smallest detectable change (SDC). A total of 108 bone erosions and 99 enthesiophytes were detected at baseline. Three new bone erosions but no new enthesiophytes were evident at 5 years. A significant increase in mean (±SD) erosion (0.58 ± 1.50 mm3, P < 0.001) and enthesiophyte (0.47 ± 0.76 mm3, P < 0.001) volume was observed. Erosion and enthesiophyte progression were found in 37/111 (33.3%) and 50/99 (50.5%) lesions, respectively. During this 5-year period, 26 (43%) out of the 60 patients achieved sustained Disease Activity index for PSoriatic Arthritis (DAPSA) low disease activity (LDA) (SDL group, defined as achieving DAPSA-LDA at both baseline and 5 years). Fourteen (23%) out of 60 patients received a TNF inhibitor throughout the 5-year period (TNFi group). Fewer erosions progressed (12/51 [23.5%] vs 25/60 [41.7%], P = 0.047) and the increased in enthesiophyte volume was significantly less (0.28 ± 0.67 vs 0.61 ± 0.80 mm3, P = 0.048) in the SDL group than in the non-SDL group. However, no significant difference between the TNFi and non-TNFi groups was detected in terms of the change in volume or progression of bone erosion and enthesiophyte. Damage accrual in terms of bone erosion and enthesiophyte was observed in PsA patients over a period of 5 years despite receiving routine clinical care. Nonetheless, sustained control of disease activity may be able to prevent these bony damages.

    更新日期:2019-12-05
  • Secukinumab efficacy on resolution of enthesitis in psoriatic arthritis: pooled analysis of two phase 3 studies
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-04
    Laura C. Coates; Johan K. Wallman; Dennis McGonagle; Georg A. Schett; Iain B. McInnes; Philip J. Mease; Lawrence Rasouliyan; Erhard Quebe-Fehling; Darren L. Asquith; Andreas E. R. Fasth; Luminita Pricop; Corine Gaillez

    Enthesitis is one of the psoriatic arthritis (PsA) domains. Patients with enthesitis are associated with worse outcomes than those without enthesitis. The effect of secukinumab on the resolution of enthesitis in patients with PsA was explored using pooled data from the FUTURE 2 and 3 studies. Assessments of enthesitis through week 104 used the Leeds Enthesitis Index. These post hoc analyses included resolution of enthesitis count (EC = 0), median time to first resolution of enthesitis (Kaplan-Meϊer estimate), and shift analysis (as observed) of baseline EC (1, 2, or 3–6) to full resolution (FR), stable (similar or reduction of EC), or worse (EC > baseline). Efficacy outcomes (ACR, PASI, HAQ-DI, SF-36 PCS, and DAS28-CRP) were assessed in patients with or without baseline enthesitis. Results are reported for secukinumab 300 and 150 mg in the overall population and by prior TNFi treatment. A total of 65% (466/712) of patients had baseline enthesitis. In the overall population, FR was achieved as early as week 16 in 65% (300 mg) and 56% (150 mg) versus 44% (placebo) patients, with further improvements to 91% (300 mg) and 88% (150 mg) at week 104. The majority (89%) of patients without enthesitis at baseline maintained this status at week 104. Median days to resolution of EC were shorter with secukinumab 300 and 150 mg versus placebo (57 and 85 vs 167 days, respectively). In patients with EC of 1 or 2, shift analysis from baseline to week 24 showed that more patients achieved FR with secukinumab 300 mg and 150 mg versus placebo, whereas no difference between secukinumab and placebo was shown in the more severe patients with EC of 3–6. Increases in proportions of patients with FR were observed with secukinumab irrespective of the severity of EC from baseline to week 104. Improvements in efficacy outcomes were similar in patients with or without enthesitis treated with secukinumab 300 mg. Secukinumab provided early and sustained resolution of enthesitis in patients with PsA over 2 years. Secukinumab 300 mg provided higher resolution than 150 mg in patients with more severe baseline EC and showed similar overall efficacy in patients with or without enthesitis. FUTURE 2: ClinicalTrials.gov, NCT01752634 (date of study registration: December 19, 2012), and EudraCT, 2012-004439-22 (date of study registration: December 12, 2012) FUTURE 3: ClinicalTrials.gov, NCT01989468 (date of study registration: November 21, 2013), and EudraCT, 2013-004002-25 (date of study registration: December 17, 2013)

    更新日期:2019-12-05
  • Diagnostic performance of serum cystatin C and complement component 1q in lupus nephritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-04
    Bei Xu; Ya-mei Zhang; Yu-wei Yang; Yun-shuang Liu; Jia-fu Feng

    The information concerning non-invasive, easily obtainable, and accurate biomarkers for diagnosis of lupus nephritis (LN) is extremely limited. The aim of this study was to evaluate the diagnostic performance of cystatin C (CysC) and complement component 1q (C1q) for LN. A case-control study that included 905 patients with systemic lupus erythematosus (SLE) without LN (group SLE), 334 patients with active lupus nephritis (group LNA), 255 patients with inactive lupus nephritis (group LNI), and 497 healthy individuals (group HC) was performed in Mianyang Central Hospital from March 2017 to December 2018. The serum levels of CysC, C1q, urea (Urea), and creatinine (Creat) were measured, and 2 estimated glomerular filtration rates (eGFRCysC and eGFRCreat) were calculated by equations which were based on serum CysC established by our group and the modification of diet in renal disease (MDRD), respectively. ANOVA analysis or Kruskal-Wallis test was used for comparing the differences among the groups, and receiver operating characteristic (ROC) curve was applied to identify the diagnostic efficiencies of individual or combined multiple indicators. Significantly elevated CysC and decreased C1q were observed in the LNA and LNI groups, which was in contrast to their levels in the SLE and HC groups. CysC (AUC = 0.906) or eGFRCysC (AUC = 0.907) assessed the highest diagnostic performance on LNA when detected individually, followed by C1q (AUC = 0.753). Joint utilization of C1q and CysC achieved very good performance (AUC = 0.933) which approximated to the best one observed in the combinations of C1q, Urea, CysC, eGFRCreat, and Creat (AUC = 0.975). The separately detected CysC (eGFRCysC) and C1q were superior to the conventional biomarkers Urea, Creat, and eGFRCreat in the diagnosis of LNA. Moreover, although the combined detection of Urea, Creat, C1q, CysC, and eGFRCreat had the greatest diagnostic performance, the joint utilization of CysC and C1q could be prioritized for rapid discrimination of LNA if the economic burden is taken into consideration.

    更新日期:2019-12-05
  • Circulating calprotectin (S100A8/A9) is higher in rheumatoid arthritis patients that relapse within 12 months of tapering anti-rheumatic drugs
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-05
    Emma C. de Moel; Jürgen Rech; Michael Mahler; Johannes Roth; Thomas Vogl; Anne Schouffoer; Robbert J. Goekoop; Tom W. J. Huizinga; Cornelia F. Allaart; René E. M. Toes; Georg Schett; Diane van der Woude

    To investigate whether calprotectin (S100A8/A9 or MRP8/14), an inflammatory complex released by monocytes, could indicate residual subclinical inflammation in rheumatoid arthritis (RA) patients who are in stable remission on disease-modifying anti-rheumatic drugs (DMARDs) and serve as a marker for disease flare after DMARD tapering. We used data from two trials. Patients from the IMPROVED study had early (< 2 years) RA, and when they achieved disease activity score remission (DAS44 < 1.6), they stopped methotrexate to attempt drug-free remission. Patients from the RETRO study had established RA in stable remission (DAS28 < 2.6) and either tapered by 50% or stopped (biological or conventional) DMARDs. Circulating calprotectin at the tapering time point was determined by ELISA, and its predictive value for flare (loss of remission) within 12 months of DMARD tapering/stopping was determined. In both IMPROVED (n = 104) and RETRO (n = 57), patients that flared within 12 months had higher calprotectin at the moment of DMARD tapering/stopping. Twofold higher calprotectin at the moment of DMARD tapering/stopping was associated with an increased risk (odds ratio) of flare of 1.07 (95% CI 0.98–1.18, p = 0.14) in the IMPROVED and 3.62 (95% CI 1.76–7.46, p < 0.001) in the RETRO. Correcting for clinical predictors of flare (DAS at study inclusion, anti-CCP2 positivity, gender) did not change these estimates. The area under the receiver operating curve of calprotectin levels for predicting flare within 12 months was 0.63 (95% CIs 0.51–0.76) in the IMPROVED study and 0.80 (95% CIs 0.69 to 0.92) in the RETRO study. Circulating calprotectin levels in RA patients in remission on DMARDs are higher in patients that will flare upon DMARD tapering/stopping. Since the differences between the cohorts precluded definitive conclusions, more research is needed to determine whether calprotectin has prognostic value in predicting flare after attempting drug tapering in RA. IMPROVED, ISRCTN11916566. RETRO, 2009-015740-42.

    更新日期:2019-12-05
  • Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-05
    Spencer I. Danto; Negin Shojaee; Ravi Shankar P. Singh; Cheryl Li; Steven A. Gilbert; Zorayr Manukyan; Iain Kilty

    PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects. Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states. Study 2 (NCT02485769) was a 14-day, placebo-controlled, MAD study of PF-06650833 IR 25 to 750 mg twice daily, IR 1000 mg four times per day, IR 330 mg three times per day, and MR 300 mg QD. PF-06650833 was generally well tolerated, with no dose-limiting treatment-emergent adverse events (TEAEs) identified in either study. TEAEs were generally mild in severity, with headache, gastrointestinal disorders, and acne most commonly reported. No serious AEs or deaths were reported. A maximum tolerated dose was not established in either study. In the SAD study, food intake delayed absorption of IR 30 mg and increased total exposure by 33%. Delayed absorption was achieved with the MR formulation (Tmax of 1 h versus 8 h for IR 100 mg and MR 100 mg formulations, respectively). Food had no effect on total exposure for MR 30 mg, but reduced half-life 1.8-fold and increased Cmax by 62%. In the MAD study, accumulation ranged from 0.9-fold to 1.4-fold for AUCtau and 0.9-fold to 1.3-fold for Cmax. Less than 1% of the dose was recovered unchanged in urine for all dose groups, with renal clearance ranging from 14 to 23 mL/min for IR < 750 mg and MR 300 mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR ≥ 250 mg and MR 300 mg. Based on the cholesterol/hydroxycholesterol ratio, no apparent CYP3A induction or inhibition was observed. PF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases. Clinicaltrials.gov, NCT02224651, registered 25 August 2014; NCT02485769, registered 30 June 2015

    更新日期:2019-12-05
  • Validation of prediction models of severe disease course and non-achievement of remission in juvenile idiopathic arthritis: part 1—results of the Canadian model in the Nordic cohort
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-05
    Veronika Rypdal; Jaime Guzman; Andrew Henrey; Thomas Loughin; Mia Glerup; Ellen Dalen Arnstad; Kristiina Aalto; Marite Rygg; Susan Nielsen; Troels Herlin; Anders Fasth; Lillemor Berntson; Martin Rypdal; Ellen Nordal

    Models to predict disease course and long-term outcome based on clinical characteristics at disease onset may guide early treatment strategies in juvenile idiopathic arthritis (JIA). Before a prediction model can be recommended for use in clinical practice, it needs to be validated in a different cohort than the one used for building the model. The aim of the current study was to validate the predictive performance of the Canadian prediction model developed by Guzman et al. and the Nordic model derived from Rypdal et al. to predict severe disease course and non-achievement of remission in Nordic patients with JIA. The Canadian and Nordic multivariable logistic regression models were evaluated in the Nordic JIA cohort for prediction of non-achievement of remission, and the data-driven outcome denoted severe disease course. A total of 440 patients in the Nordic cohort with a baseline visit and an 8-year visit were included. The Canadian prediction model was first externally validated exactly as published. Both the Nordic and Canadian models were subsequently evaluated with repeated fine-tuning of model coefficients in training sets and testing in disjoint validation sets. The predictive performances of the models were assessed with receiver operating characteristic curves and C-indices. A model with a C-index above 0.7 was considered useful for clinical prediction. The Canadian prediction model had excellent predictive ability and was comparable in performance to the Nordic model in predicting severe disease course in the Nordic JIA cohort. The Canadian model yielded a C-index of 0.85 (IQR 0.83–0.87) for prediction of severe disease course and a C-index of 0.66 (0.63–0.68) for prediction of non-achievement of remission when applied directly. The median C-indices after fine-tuning were 0.85 (0.80–0.89) and 0.69 (0.65–0.73), respectively. Internal validation of the Nordic model for prediction of severe disease course resulted in a median C-index of 0.90 (0.86–0.92). External validation of the Canadian model and internal validation of the Nordic model with severe disease course as outcome confirm their predictive abilities. Our findings suggest that predicting long-term remission is more challenging than predicting severe disease course.

    更新日期:2019-12-05
  • Arthritis sensory and motor scale: predicting functional deficits from the clinical score in collagen-induced arthritis
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-04
    Anne-Laure Mausset-Bonnefont; Maïlys Cren; Rita Vicente; Julie Quentin; Christian Jorgensen; Florence Apparailly; Pascale Louis-Plence

    In the collagen-induced arthritis (CIA) mouse model, inflammation readouts are usually quantified using operator-dependent clinical scoring systems, and no systematic relationship with functional deficits has been detected. In this study, we extensively quantified sensory and motor deficits in CIA mice during natural disease progression and therapeutic treatment. Then, we used these data to build a scale to predict functional deficits on the basis of the classical clinical score. Using the CIA mouse model, we longitudinally screened multiple approaches to assess locomotion (open field test, Catwalk™), sensitivity (Von Frey, Hargreaves, static weight-bearing tests), and inflammation (skin temperature), and identified the most accurate tests to correlate sensory and motor deficits with disease severity, measured by clinical score. We then used these tests to characterize functional deficits in control (naïve and mice injected with complete Freund’s adjuvant) and CIA mice, either untreated or treated with methotrexate to prevent functional deficits. By mathematical approaches, we finally investigated the relationship between functional deficits and clinical score. We found that the functional disability scores obtained with the open field, Catwalk™, Hargreaves, and skin temperature tests significantly correlated with the clinical score in CIA mice, either untreated or treated with methotrexate. Mathematical correlation showed that motor deficits, robustly characterized by two different tests, were twice more responsive than thermal sensitivity deficits. We propose the arthritis sensory and motor (ArthriSM) scale as a new theranostic tool to predict motor and sensory deficit based on the clinical score, in the experimental mouse model of CIA. This ArthriSM scale may facilitate the transfer of knowledge between preclinical and clinical studies.

    更新日期:2019-12-04
  • Interferon score is increased in incomplete systemic lupus erythematosus and correlates with myxovirus-resistance protein A in blood and skin
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-02
    Wietske M. Lambers; Karina de Leeuw; Berber Doornbos-van der Meer; Gilles F.H. Diercks; Hendrika Bootsma; Johanna Westra

    Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients. Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators myxovirus-resistance protein A (MxA), IFN-γ-induced protein 10 (IP-10), and monocyte chemoattractant protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA. IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001). IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.

    更新日期:2019-12-02
  • ALW peptide ameliorates lupus nephritis in MRL/lpr mice
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-02
    Huixia Wang; Mei Lu; Siyue Zhai; Kunyi Wu; Lingling Peng; Jie Yang; Yumin Xia

    Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus. Anti-double-stranded (ds) DNA immunoglobulin G (IgG) plays a pivotal role in the pathogenesis of LN. Currently, there are various therapies for patients with LN; however, most of them are associated with considerable side effects. We confirmed previously that ALW (ALWPPNLHAWVP), a 12-amino acid peptide, inhibited the binding of polyclonal anti-dsDNA antibodies to mesangial cells and isolated glomeruli in vitro. In this study, we further investigate whether the administration of ALW peptide decreases renal IgG deposition and relevant damage in MRL/lpr lupus-prone mice. Forty female MRL/lpr mice were randomly divided into four groups. The mice were intravenously injected with D-form ALW peptide (ALW group), scrambled peptide (PLP group), and normal saline (NaCl group) or were not treated (blank group). The IgG deposition, the histopathologic changes, and the expressions of profibrotic factors were analyzed in the kidney of MRL/lpr mice. Compared with the other groups, glomerular deposition of IgG, IgG2a, IgG2b, and IgG3 was decreased in the ALW group. Moreover, ALW administration attenuated renal histopathologic changes in MRL/lpr mice, including mesangial proliferation and infiltration of inflammatory cells. Furthermore, the expressions of profibrotic cytokines, such as transforming growth factor-beta1 (TGF-β1) and platelet-derived growth factor B (PDGF-B), decreased in the serum and kidney tissue of ALW-treated mice. Our study demonstrated that ALW peptide ameliorates the murine model of LN, possibly through inhibiting renal IgG deposition and relevant tissue inflammation and fibrosis.

    更新日期:2019-12-02
  • Inflammatory stays inflammatory: a subgroup of systemic sclerosis characterized by high morbidity and inflammatory resistance to cyclophosphamide
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-02
    Aleksey Mitev; Lisa Christ; Daria Feldmann; Moritz Binder; Kim Möller; Anna-Maria Kanne; Thomas Hügle; Peter M. Villiger; Reinhard E. Voll; Stephanie Finzel; Florian Kollert

    Elevated levels of C-reactive protein (CRP) in systemic sclerosis (SSc) have been linked to early inflammatory stages of the disease. This study has been designed to investigate CRP levels longitudinally in a cohort of SSc patients and to correlate these findings with comorbidities and disease characteristics. In this retrospective study, patients with SSc treated at the outpatient clinic of the Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, were analyzed. Only patients with at least three consecutive visits and at least 1 year follow-up were included in this study. CRP serum levels were measured at every visit and categorized as positive if CRP concentrations were ≥ 5 mg/l. Subjects with elevated CRP levels at more than 80% of visits were defined as inflammatory SSc. The longitudinal CRP profiles were correlated with disease characteristics and comorbidities. A total of 1815 consecutive visits of 131 SSc patients were analyzed. Over the observed time span (7.6 (1.0–19.5) years), 18.3% (n = 24) of patients had continuously elevated CRP levels (inflammatory SSc), whereas in 29% (n = 38), CRP levels were always in the normal range. There was no association between disease duration and CRP levels at first visit. Inflammatory SSc was associated with male gender (p = 0.022), anti-Scl-70 antibodies (p = 0.009), diffuse cutaneous SSc (p = 0.036), pulmonary fibrosis (p < 0.001), rheumatoid arthritis (p = 0.007), and cardiac arrhythmia (p = 0.048). Moreover, patients with inflammatory SSc revealed higher modified Rodnan skin scores (p < 0.001); lower forced vital capacity (FVC) (p < 0.001), total lung capacity (p = 0.001), and diffusing capacity (p = 0.008); and faster decline of FVC per year (p = 0.007). Even treatment with cyclophosphamide (CYC) did not decrease CRP levels (p = 0.754). Inflammatory SSc is characterized by a more severe phenotype, high morbidity, and a large proportion of male patients. Even treatment with CYC does not alter CRP levels in this subpopulation with a high unmet medical need.

    更新日期:2019-12-02
  • Effects of upadacitinib on patient-reported outcomes: results from SELECT-BEYOND, a phase 3 randomized trial in patients with rheumatoid arthritis and inadequate responses to biologic disease-modifying antirheumatic drugs
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-12-02
    Vibeke Strand; Michael Schiff; Namita Tundia; Alan Friedman; Sebastian Meerwein; Aileen Pangan; Arijit Ganguli; Mahesh Fuldeore; Yan Song; Janet Pope

    Patient-reported outcomes (PROs) are important when evaluating treatment benefits in rheumatoid arthritis (RA). We compared upadacitinib, an oral, selective JAK-1 inhibitor, with placebo to assess clinically meaningful improvements in PROs in patients with RA who have had inadequate responses to biologic disease-modifying antirheumatic drugs (bDMARD-IR). PRO responses between upadacitinib 15 mg or 30 mg and placebo were evaluated at week 12 from the SELECT-BEYOND trial. Improvement was determined by measuring Patient Global Assessment of Disease Activity (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36), duration and severity of morning (AM) stiffness, and Insomnia Severity Index (ISI). Least squares mean changes and percentage of patients reporting improvements ≥ minimum clinically important differences (MCID) and scores greater than or equal to normative values were determined. The number needed to treat (NNT) to achieve clinically meaningful improvements was calculated. In 498 patients, both upadacitinib doses resulted in statistically significant changes from baseline versus placebo in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 7 of 8 SF-36 domains (15 mg), 6 of 8 SF-36 domains (30 mg), and AM stiffness duration and severity. Compared with placebo, more upadacitinib-treated patients reported improvements ≥ MCID in PtGA, pain, HAQ-DI, SF-36 PCS, 7 of 8 SF-36 domains (15 mg), 5 of 8 SF-36 domains (30 mg), AM stiffness duration and severity, and ISI (30 mg) and scores ≥ normative values in HAQ-DI and SF-36 domains. Across most PROs, NNTs to achieve MCID with upadacitinib ranged from 4 to 7 patients. In bDMARD-IR RA patients, upadacitinib (15 mg or 30 mg) improved multiple aspects of quality of life, and more patients reached clinically meaningful improvements approaching normative values compared with placebo. The trial is registered with ClinicalTrials.gov (NCT02706847), registered 6 March 2016.

    更新日期:2019-12-02
  • Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment response in patients with inflammatory joint diseases: data from the NOR-DMARD study
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-11-29
    Johanna Elin Gehin; Guro Løvik Goll; David John Warren; Silje Watterdal Syversen; Joseph Sexton; Eldri Kveine Strand; Tore Kristian Kvien; Nils Bolstad; Elisabeth Lie

    To identify a therapeutic target interval for certolizumab pegol drug levels and examine the influence of anti-drug antibodies in patients with inflammatory joint diseases. Certolizumab pegol and anti-drug antibody levels were measured in serum samples collected after 3 months of certolizumab pegol treatment in 268 patients with inflammatory joint diseases (116 axial spondyloarthritis, 91 rheumatoid arthritis and 61 psoriatic arthritis) in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score Clinically important improvement in axial spondyloarthritis, European League Against Rheumatism good/moderate response in rheumatoid arthritis, and improvement in 28-joint Disease Activity Score of ≥ 0.6 in PsA. Serum drug levels and anti-drug antibodies were analysed using automated in-house assays. Certolizumab pegol serum levels varied considerably between individuals (median (IQR) 32.9 (17.3–43.9) mg/L). Certolizumab pegol level ≥ 20 mg/L was associated with treatment response for the total inflammatory joint disease population, with odds ratio (OR) 2.3 (95% CI 1.2–4.5, P = 0.01) and OR 1.9 (95% CI 1.0–3.5, P = 0.05) after 3 and 6 months of treatment, respectively. For individual diagnoses, this association was most consistent for axial spondyloarthritis, with OR 3.4 (95% CI 1.0–11.1, P < 0.05) and OR 3.3 (95% CI 1.0–10.8, P < 0.05), respectively. Certolizumab pegol level > 40 mg/L was not associated with any additional benefit for any of the diagnoses. Anti-drug antibodies were detected in 6.1% (19/310) of samples and were associated with low certolizumab pegol levels (P < 0.01). Serum certolizumab pegol levels 20–40 mg/L were associated with treatment response in inflammatory joint diseases. Our study is the first to show this association in axial spondyloarthritis and psoriatic arthritis patients. The results suggest a possible benefit of therapeutic drug monitoring in patients with inflammatory joint disease on certolizumab pegol treatment. NCT01581294, April 2012.

    更新日期:2019-11-30
  • Association between pain phenotype and disease activity in rheumatoid arthritis patients: a non-interventional, longitudinal cohort study
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-11-29
    P. M. ten Klooster; N. de Graaf; H. E. Vonkeman

    In well-controlled rheumatoid arthritis (RA) without significant joint damage, a substantial proportion of patients complain of persistent pain. Previous studies have identified different pain phenotypes in RA, in which non-nociceptive pain phenotypes are associated with higher concurrent disease activity scores. In this longitudinal study, we explored associations between pain phenotypes and long-term disease activity outcome in RA patients. Secondly, we explored whether pain phenotype is associated with comorbid conditions. One hundred eighty established RA patients were classified with a nociceptive (61%) or a non-nociceptive (39%) pain phenotype, based on their responses to the painDETECT-questionnaire. Two years of clinical follow-up data on disease activity outcomes were collected. Information on comorbid diseases was derived from electronic patient files. Patients with a non-nociceptive pain phenotype showed higher mean disease activity scores (DAS28, 2.57; 95% CI, 2.37–2.77 vs. 2.11; 95% CI, 1.94–2.27; p < 0.001) and a twofold lower chance of achieving sustained DAS28 remission (OR = 0.49; 95% CI, 0.26–0.92; p = 0.020). Only the tender joint count and patient global health significantly differed between the pain phenotype groups. Patients with a non-nociceptive pain phenotype had more often been diagnosed with concurrent fibromyalgia (9.9% vs. 0.9%; p = 0.007) and other pain-associated comorbid diseases (52.1% vs. 35.8%; p = 0.030) compared with patients with a nociceptive pain phenotype. This longitudinal study showed consistently worse long-term disease activity outcomes in RA patients with a non-nociceptive pain phenotype which appeared to be mainly due to differences in the subjective components of the disease activity score. The DREAM cohort study is registered in the Netherlands Trial Register: NTR578.

    更新日期:2019-11-30
  • NEMO score in nailfold videocapillaroscopy is a good tool to assess both steady state levels and overtime changes of disease activity in patients with systemic sclerosis: a comparison with the proposed composite indices for this disease status entity
    Arthritis Res. Ther. (IF 4.148) Pub Date : 2019-11-29
    Francesca Pignataro; Wanda Maglione; Antonina Minniti; Domenico Sambataro; Gianluca Sambataro; Francesco Campanaro; Gabriele Valentini; Claudio Vitali; Nicoletta Del Papa

    In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages (MHEs) and microthromboses (MTs), observed in nailfold videocapillaroscopy was a good indicator of the steady state level of disease activity (DA) in patients with systemic sclerosis (SSc) when the European Scleroderma Study Group (EScSG) index was considered the gold standard. To verify whether the NEMO score could be (i) a valid tool to assess DA, even when the modified European Scleroderma Trials and Research (EUSTAR) index was considered to be the comparator, and (ii) a sensitive method to capture the DA overtime changes. The NEMO score and the EScSG and EUSTAR indices were contemporarily assessed at baseline (T0) and after a follow-up of 4–56 months (T1) in 98 patients with SSc. The differences (Δ) between the T1 and T0 values of the NEMO score and the EScSG and EUSTAR indices were calculated and compared to each other. NEMO score values were very closely correlated with the corresponding values of the EScSG and EUSTAR indices both at T0 and T1 observations (p < 0.0001 in all cases with the exception of the correlation with EScSG values at T1 (p < 0.03)). The values of the two composite DA indices were also strictly related to each other in both T0 and T1 observations (p < 0.0001). Receiver operating characteristic (ROC) curve analysis showed the NEMO score had a good sensitivity and specificity in classifying patients with a predefined level of DA (scores ≥ 3.0 and ≥ 2.5 for the EScSG and EUSTAR indices, respectively, p < 0.0001 in both cases). Δ values of the NEMO score were significantly correlated with the corresponding values of both the EScSG and EUSTAR indices. Weighted Cohen’s k level of agreement between Δ values of the NEMO score and those of the EScSG and EUSTAR indices was moderate (0.55 and 0.59, respectively). NEMO score proves to be a feasible, non-invasive, and valid tool to assess steady state levels and changes over time of DA in patients with SSc. Thus, it can represent an alternative or complementary method to measure this disease status entity in this disorder.

    更新日期:2019-11-30
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