BMC Rheumatology

Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.

Julie M. Parmentier

Jeff Voss

Candace Graff

Annette Schwartz

Maria Argiriadi

Michael Friedman

Heidi S. Camp

Robert J. Padley

Jonathan S. George

Deborah Hyland

Matthew Rosebraugh

Neil Wishart

Lisa Olson

Andrew J. Long

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

体外和体内表征乌帕他尼布（ABT-494）的JAK1选择性

Abstract Objectives Inflammatory arthritis (IA) has been associated with various problems related to male sexual and reproductive health (SRH). However, addressing these issues in the clinic remains a challenge. In this study, we aimed to describe the viewpoints of rheumatologists and male patients with IA regarding the aspects that influence their communication about SRH. Methods Rheumatologists and adult men with IA were invited to participate. This study uses Q-methodology, a mixed methods approach to systematically study subjectivity. Participants ranked 32 aspects according to their degree of influence (least-most influence) in addressing SRH and were then interviewed. Factor analysis was used to identify common patterns in the rankings. These patterns were interpreted as the different viewpoints of rheumatologists and male patients, supported by the qualitative data from the interviews. To obtain more generalizable results, the study was conducted in two countries with different socio-cultural backgrounds and healthcare systems, The Netherlands and Mexico. Results 30 rheumatologists and 30 men with IA were included in each country. The analysis revealed three viewpoints in each group. Rheumatologists are more likely to be influenced by aspects such as the patient’s desire to become a father or the patients’ (young) age, but patients by a much more diverse pool of aspects, such as potential side effects of medication on their sexual function. Conclusions This study identified different viewpoints on the aspects that influence discussing SRH between rheumatologists and male patients, and important differences in viewpoints between both groups. Further research is needed to reach consensus on how and when rheumatologists and male patients should discuss SRH.

L. F. Perez-Garcia

E. Röder

H. Pastoor

A. C. Lozada-Navarro

I. Colunga-Pedraza

T. Vargas-Aguirre

J. van Exel

A. Vargas-Guerrero

R. J. E. M. Dolhain

Discussing male sexual and reproductive health in the rheumatology outpatient clinic: a Q-methodology study

风湿科门诊男性性健康与生殖健康讨论：一项Q方法学研究

Cholesterol embolism causes various organ dysfunctions, including skin, kidney, and gastrointestinal tract dysfunction, as well as immunological abnormalities, such as hypocomplementemia and eosinophilia. However, only a few cases of vasculitis accompanied by cholesterol embolism have been reported. We present the case of an 82-year-old man with cholesterol embolism who also developed small-vessel vasculitis of the skin and muscles. The patient had a persistent fever, and blood tests showed eosinophilia and hypocomplementemia. Two months later, the patient developed a skin rash and myalgia in the thighs. Magnetic resonance imaging of the thighs revealed diffuse intramuscular hyperintensities on T2-weighted images and short tau inversion recovery sequences in the hamstrings and quadriceps femoris. Histological findings of the skin and muscle revealed small-vessel vasculitis, and random skin biopsy revealed cholesterol embolism. We diagnosed the patient with cholesterol embolism accompanied by small-vessel vasculitis of the skin and femoral muscles. Methylprednisolone was administered intravenously, and oral prednisolone was initiated. Muscle tenderness improved rapidly after the initiation of glucocorticoid therapy. However, he developed superior mesenteric artery embolization and died. Our case demonstrates that cholesterol embolism can be accompanied by small-vessel vasculitis of the skin and muscles.

Daichi Umemoto

Ichizo Nishino

Daisuke Yamashita

Naoto Ishimaru

Hiroaki Nishioka

Small-vessel vasculitis associated with cholesterol embolism: a case report

胆固醇栓塞相关小血管血管炎病例报告

Abstract Background Thermography is an emerging imaging modality which allows for a quick and objective measure of joint surface temperature in patients with rheumatoid arthritis (RA). To date, there are no published studies comparing thermography with ultrasonography in the subclinical assessment of joint inflammation at the wrist of patients with RA, and no published data on inter-rater reliability for multiple raters for thermographic assessment at the RA wrist. In our study comparing thermography and ultrasonography at the RA wrist, we aim to determine if thermography can detect subclinical synovitis. Additionally, we performed inter-reliability testing (multiple raters) for both thermography and ultrasonography. Methods Thermographic (average (Tavg), maximum (Tmax) and minimum (Tmin) temperatures) and ultrasound (total grey-scale (TGS) score and total power Doppler (TPD) scores) parameters were compared between two patient groups: Asymptomatic Group (with non-swollen and non-tender wrists) and Symptomatic Group (with swollen and/or tender wrists). Among Asymptomatic Group patients, thermographic parameters were compared between those with and without wrist joint recess(es) having ultrasound synovitis (PD ≥ 1 or GS ≥ 2); Spearman’s correlation and simple linear regression were used to study the relationship between thermographic and ultrasound parameters. Intra-class correlation coefficient (ICC) was used for inter-rater reliability calculation. Results Eighty-seven RA patients’ right wrists were imaged in this cross-sectional study. Thermographic temperatures, TPD and TGS scores were all significantly ( p &lt; 0.05) greater among Symptomatic Group versus Asymptomatic Group patients. Among Asymptomatic Group patients, thermographic temperatures were all significantly higher ( P &lt; 0.01) in wrists having joint recess(es) with ultrasound PD ≥ 1 or GS ≥ 2, while all thermographic parameters correlated significantly with TPD (correlation coefficient ranging from 0.43 to 0.48, p &lt; 0.001) and TGS (correlation coefficient ranging from 0.33 to 0.37, p &lt; 0.01). The ICC values based on a subset of images obtained for inter-reliability testing were high for thermography (0.994 to 0.998) and ultrasonography (0.933 to 0.952). Conclusions Swollen and/or tender RA wrists displayed greater thermographic and ultrasound-detected joint inflammation. At clinically quiescent (non-swollen; non-tender) wrists, thermographic temperatures significantly correlated with ultrasound-detected joint inflammation. Clinical trial number Not applicable.

York Kiat Tan

Gek Hsiang Lim

Chin Chin Ooi

Voon Chee Ma

Bimal Mayur Kumar Vora

Thermographic and ultrasound assessment in patients with rheumatoid arthritis: can thermography detect subclinical synovitis at the wrist?

类风湿性关节炎患者的热成像和超声评估：热成像能否检测手腕的亚临床滑膜炎？

Chronic invasive rhinosinusitis with facial bone damage is a common cause of functional and social impairment in granulomatosis with polyangiitis (GPA) patients. To the best of our knowledge, there is no clinical or laboratory biomarker to predict bone damage. This case-control study included 90 patients with GPA and 270 health controls (HCs). Patients were categorized according to the presence of tomographic facial bone erosions. Frequency of RANKL and osteoprotegerin single nucleotide polymorphisms (SNPs), analyzed by real-time polymerase chain reaction, were compared between patients and HCs, and between patients with and without bone damage. Clinical, therapeutic, and laboratory data were analyzed. Facial bone erosion was observed in 55.5% of patients. No difference was found in the frequency of SNPs between patients with GPA and HCs. GPA patients were compared according to the presence or absence of bone damage, and a difference was found in the frequencies of osteoprotegerin G1181C (rs2073618) and RANKL A290G (rs2277438). A multivariate analysis showed that the CC genotype of osteoprotegerin 1181 was independently associated with bone erosion (OR = 3.95, CI95%=1.20–13.00, P = 0.02), as were the presence of the G allele in RANKL A290G (OR = 6.13, CI95%=1.95–19.26, P = 0.002) and higher disease duration (OR = 1.08, CI95%=1,01-1.15, P = 0.04). SNPs in osteoprotegerin G1181C and RANKL A290G may play a role in the development of destructive rhinosinusitis in patients with GPA. Genetic assessment may be useful for identifying high-risk individuals. This observational study might work as a basis for further research to better understand this association and clinical trials using RANKL/osteoprotegerin as therapeutic targets.

Marília A. D. Furquim

Bidossessi W. Hounkpe

Valéria F. Caparbo

Henrique A. M. Giardini

Carmen S. V. Barbas

Diogo S. Domiciano

Samuel K. Shinjo

Rosa M. R. Pereira

Association between osteoprotegerin and RANKL single nucleotide polymorphisms and destructive rhinosinusitis in patients with granulomatosis with polyangiitis

骨保护素与RANKL单核苷酸多态性与肉芽肿性多血管炎患者破坏性鼻窦炎的关联

Abstract Background Healthy lifestyle habits (regular physical activity, a healthy diet, no smoking and non-hazardous alcohol consumption) alongside pharmacological treatment can lower the risk of cardiovascular diseases and improve symptoms and quality of life in patients with rheumatoid arthritis (RA). Therefore, healthcare professionals in rheumatology care are urged to discuss lifestyle habits with all patients. The aim of this study was to explore patients’ perceptions of lifestyle discussions in early rheumatology care. Methods Individual interviews were conducted with 20 patients with RA, 14 women and six men, aged 23 to 77 years, and with a mean disease duration of 2.4 years. All lifestyle discussions were performed during the first year with RA. A qualitative content analysis was performed. Results An overarching theme emerged, exploring how patients with RA perceived lifestyle discussions as facilitating self-management. Three categories illustrated this: (1) the usefulness of lifestyle discussions depended on the individual patient’s preferences and prioritization for lifestyle support; (2) the design of lifestyle discussions should be based on a person-centred approach, incorporating personalized lifestyle information and providing structured and recurrent support; (3) the outcomes of lifestyle discussions should contribute to enhanced knowledge and motivation for making healthy lifestyle changes. Conclusion Lifestyle discussions in early rheumatology care should, according to patients with RA, be based on a person-centred approach, be tailored to each patient’s preferences and needs, and have outcomes focusing on patient support for healthy lifestyle changes, all essential elements to facilitate self-management. The present findings can be used to guide the development and implementation of more person-centred lifestyle approaches targeted to facilitate lifestyle changes and benefit cardiovascular disease risk management in early rheumatology care.

Klara Drake af Hagelsrum

Ingrid Larsson

Ann Bremander

Jon T. Einarsson

Elisabet Lindqvist

Elisabeth Mogard

Lifestyle discussions facilitate self-management in RA: a qualitative study of patients’ perceptions

生活方式讨论促进类风湿性关节炎患者的自我管理：一项关于患者感知的定性研究

Intermittent fasting (IF) has shown benefits in various pathological conditions. Although its anti-inflammatory potential has been recognized, its effects on the mechanism underlying rheumatoid arthritis (RA) remain insufficiently characterized. This study aimed to investigate the effects of IF in a murine model of RA.

Rubén Cuevas-Martínez

Susana Aideé González-Chávez

Mercedes Bermúdez

Joan Sebastian Salas-Leiva

Gregorio Vázquez-Olvera

Luis Carlos Hinojos-Gallardo

Eduardo Chaparro-Barrera

César Pacheco-Silva

Consuelo Romero-Sánchez

Carlos Esteban Villegas-Mercado

César Pacheco-Tena

Intermittent fasting reduces inflammation and joint damage in a murine model of rheumatoid arthritis: insights from transcriptomic and metagenomic analyses

间歇性禁食减轻小鼠类风湿性关节炎模型中的炎症和关节损伤：转录组学和宏基因组学分析的见解

Abbreviation	BMC Rheumatol
Journal Impact	2.17
Quartiles(Global)	RHEUMATOLOGY(Q3)

ISSN	2520-1026
h-index	22

Publication Information	Publisher: BioMed Central Ltd，Publishing cycle: ，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2017，Proportion of original research papers: 96.67%，Self Citation Rate:4.80%， Gold OA Rate: 99.48%
Journal Fees	$2090Details
Average review cycle	网友分享经验：15 Weeks

BMC Rheumatology

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In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

Discussing male sexual and reproductive health in the rheumatology outpatient clinic: a Q-methodology study

Small-vessel vasculitis associated with cholesterol embolism: a case report

Thermographic and ultrasound assessment in patients with rheumatoid arthritis: can thermography detect subclinical synovitis at the wrist?

Association between osteoprotegerin and RANKL single nucleotide polymorphisms and destructive rhinosinusitis in patients with granulomatosis with polyangiitis

Discussing male sexual and reproductive health in the rheumatology outpatient clinic: a Q-methodology study

Small-vessel vasculitis associated with cholesterol embolism: a case report

Lifestyle discussions facilitate self-management in RA: a qualitative study of patients’ perceptions

Intermittent fasting reduces inflammation and joint damage in a murine model of rheumatoid arthritis: insights from transcriptomic and metagenomic analyses

Association between osteoprotegerin and RANKL single nucleotide polymorphisms and destructive rhinosinusitis in patients with granulomatosis with polyangiitis