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ID PMID Title PublicationDate abstract
33251163 Salivary Oral Microbiome of Children With Juvenile Idiopathic Arthritis: A Norwegian Cross 2020 BACKGROUND: The oral microbiota has been connected to the pathogenesis of rheumatoid arthritis through activation of mucosal immunity. The objective of this study was to characterize the salivary oral microbiome associated with juvenile idiopathic arthritis (JIA), and correlate it with the disease activity including gingival inflammation. METHODS: Fifty-nine patients with JIA (mean age, 12.6 ± 2.7 years) and 34 healthy controls (HC; mean age 12.3 ± 3.0 years) were consecutively recruited in this Norwegian cross-sectional study. Information about demographics, disease activity, medication history, frequency of tooth brushing and a modified version of the gingival bleeding index (GBI) and the simplified oral hygiene index (OHI-S) was obtained. Microbiome profiling of saliva samples was performed by sequencing of the V1-V3 region of the 16S rRNA gene, coupled with a species-level taxonomy assignment algorithm; QIIME, LEfSe and R-package for Spearman correlation matrix were used for downstream analysis. RESULTS: There were no significant differences between JIA and HC in alpha- and beta-diversity. However, differential abundance analysis revealed several taxa to be associated with JIA: TM7-G1, Solobacterium and Mogibacterium at the genus level; and Leptotrichia oral taxon 417, TM7-G1 oral taxon 352 and Capnocytophaga oral taxon 864 among others, at the species level. Haemophilus species, Leptotrichia oral taxon 223, and Bacillus subtilis, were associated with healthy controls. Gemella morbillorum, Leptotrichia sp. oral taxon 498 and Alloprevotella oral taxon 914 correlated positively with the composite juvenile arthritis 10-joint disease activity score (JADAS10), while Campylobacter oral taxon 44 among others, correlated with the number of active joints. Of all microbial markers identified, only Bacillus subtilis and Campylobacter oral taxon 44 maintained false discovery rate (FDR) < 0.1. CONCLUSIONS: In this exploratory study of salivary oral microbiome we found similar alpha- and beta-diversity among children with JIA and healthy. Several taxa associated with chronic inflammation were found to be associated with JIA and disease activity, which warrants further investigation.
32529388 Clinical outcome of bi-unicompartmental knee arthroplasty for both medial and lateral femo 2020 Oct INTRODUCTION: Unicompartmental knee arthroplasty (UKA) is a well-accepted treatment for isolated unicompartmental osteoarthritis (OA) of the knee. In previous literature, it has been suggested that bi-unicompartmental knee arthroplasty (bi-UKA) which uses two UKA implants in both the medial and lateral compartments of the same knee is a feasible and viable option for the treatment of knee OA. Given the advantages of UKA treatment, it is warranted to review the literature of bi-UKA and discuss the evidence in terms of implant selection, indications, surgical techniques, and outcomes, respectively. MATERIALS AND METHODS: Following the PRISMA guidelines, PubMed, Medline, Embase, CINAHL, Web of Science, and Cochrane Library were searched for studies presenting outcome of bi-UKA. Studies were included if they reported clinical outcomes using two unicompartmental prostheses for both medial and lateral femorotibial arthritis. Studies with the addition of patellofemoral arthroplasty or concomitant soft-tissue reconstruction and those not published in English were excluded. RESULTS: In the early literature, the procedure of bi-UKA were performed for very severe OA and rheumatoid arthritis, but indications have evolved to reflect a more contemporary case-mix of knee OA patients. Both mobile and fixed bearing implants have been used, with the latter being the most frequent choice. A medial parapatellar approach for incision and arthrotomy has been the most frequently used technique. The present review found a promising clinical outcome of both simultaneous and staged bi-UKA although the number of long-term follow-up studies was limited. CONCLUSIONS: Both simultaneous and staged bi-UKA has demonstrated good functional outcomes. However, the volume and level of evidence in general is low for studies captured in this review, and the data on long-term outcomes remain limited. The present review indicates that bi-UKA is a feasible and viable surgical option for bicompartmental femorotibial OA in carefully selected patients.
33120813 Effect of downregulation of serum MMP-3 levels by traditional Chinese medicine ingredients 2020 Oct 23 BACKGROUND: A large number of clinical studies have confirmed that after treatment with traditional Chinese medicine components such as sinomenine (SIN), the matrix -metalloproteinase3 (MMP-3) level of patients with rheumatoid arthritis (RA) shows a significant decrease, whereas MMP-3 can be involved in degrading bone matrix in humans, so in the progression of bone and joint injury in patients with RA, serum MMP-3 can be used as an important biochemical marker. The traditional Chinese medicine components commonly used in clinical practice include total glucosides of paeony (TGP), SIN, and tripterygium glycosides, which have the characteristics of disease-modifyinganti-rheumatic drugs and non-steroidal anti-inflammatory drugs, while they can reduce the toxic side effects of methotrexate (MTX), and their combination with other drugs such as MTX and leflunomide (HWA486) has become an important regimen for the treatment of RA in clinical practice. Therefore, we designed this study protocol to evaluate the adjuvant effect of commonly used traditional Chinese medicine components combined with MTX in the treatment of osteoarticular injury in RA. METHODS: The search time was set from January 2000 to September 2020 in this study. EMBASE database, Cochrane Library, PubMed, Web of Science, Science Direct, Chinese National Knowledge Infrastructure, China Biology Medicine disc (CBM), Chinese Scientifific Journals Database (VIP), and Wanfang Database were used as search sources to select the traditional Chinese medicine components that reduce MMP-3 and use MTX in the treatment of RA. Clinical randomized controlled trials were used, and inclusion criteria and exclusion criteria were set for screening. In this study, MMP-3, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), cyclic peptide containing citrulline (CCP) and rheumatoid factor (RF) were used as the main outcomes, and the improvement of Disease Activity Score 28 (DAS28), joint bone mineral density, Clinical Disease Activity Index (CDAI), and other clinically relevant symptoms was selected as the secondary outcomes. Revman software version 5.3 was used for statistical analysis of data and risk assessment of deviation in this meta-analysis. In this study, one researcher performed study direction selection, literature inquiry, and literature download, and 2 independent reviewers performed literature data extraction and literature quality assessment. Dichotomized data are expressed as relative risk, continuous data are expressed as mean difference or standard mean difference, and finally fixed-effect model or random-effect model is used for synthesis according to the heterogeneity of data. RESULTS: To evaluate the effect of downregulation of MMP-3 level by traditional Chinese medicine components combined with MTX on the progression of bone injury in patients with RA by serum MMP-3, ESR, CRP, CCP, and RF. CONCLUSION: This study protocol can be used to evaluate the efficacy and safety of traditional Chinese medicine components combined with MTX in the treatment of bone injury in patients with RA. ETHICS AND DISSEMINATION: This study is a secondary study based on the published clinical research; therefore, approval from an ethics committee is not required for this study. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P), the results of this study will be published in peer-reviewed scientific journals and conference papers. REGISTRATION NUMBER:: is INPLASY202090064.
32660497 Assessment and treatment of Down syndrome-associated arthritis: a survey of pediatric rheu 2020 Jul 13 BACKGROUND: Inflammatory arthritis in children with Down syndrome (DS) was first described in 1984 and is now termed Down syndrome-associated arthritis (DA). Studies have shown that DA is under-recognized with a 19-month average delay in diagnosis. Additionally, most patients present with polyarticular, rheumatoid factor (RF) and anti-nuclear antibody (ANA) negative disease. Current therapies for juvenile idiopathic arthritis (JIA) have been used, but appear to be poorly tolerated, more toxic and less effective in patients with DA. There is currently no standardized approach to the assessment or management of DA. The objective of this study was to describe provider perspectives toward diagnostic and treatment approach of DA, to provide baseline information upon which to design future studies. METHODS: An electronic survey, organized into sections regarding individual practices of assessment and treatment approach of DA, was sent to the Pediatric Rheumatology electronic list-serv. Survey responses were voluntary and results were analyzed by descriptive statistics. RESULTS: Of 90 survey responses received, 89 were included in the analysis (one was a duplicate response). The respondents were mostly pediatric rheumatologist (94%), with greater than 10 years of experience (55%). The majority (64%) currently see 1-3 patients with DA. Most view DA as the same disease as JIA (73%), and the majority (63%) use a combination of history, exam and imaging to diagnose DA. The most ordered diagnostic tests are CBC (97%) and ESR (96%). The most used treatments include NSAIDs (94%) and methotrexate (91%) followed by anti-TNF agents (90%). Methotrexate is most administered by subcutaneous route (84%) at a dose of 15 mg/m(2) (56%). Oral corticosteroids were only used in 19% of the patients with DA. CONCLUSION: This is the first study to evaluate provider perspectives towards the diagnostic and treatment approach of DA. Most pediatric rheumatologists feel that DA and JIA are synonymous, and similar approaches to diagnosis are employed, utilizing history, physical exam, laboratory tests, and imaging modalities. DA is treated similarly to JIA with initiation of NSAIDs, disease-modifying anti-rheumatic drugs and biologic therapy. More research is needed to determine optimal screening and therapeutic approach specific to DA.
28777897 Joint Distribution and Two-Year Outcome in 347 Patients With Monoarthritis of Less Than Si 2020 May OBJECTIVE: The present study was undertaken to investigate the joint distribution and 2-year outcome of patients with recent-onset monoarthritis. METHODS: Adult patients with clinically apparent monoarthritis of ≤16 weeks' duration were included in a multicenter 2-year longitudinal study. Clinical characteristics, joint distribution, development of chronic inflammatory rheumatic disease (CIRD), as well as classification criteria according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria for RA were studied. Predictors for development of CIRD were analyzed by multivariable logistic regression analyses. RESULTS: The knee (49.3%), ankle (16.7%), and wrist (14.1%) were the most frequently affected joints among the 347 included patients. A total of 91 patients (26.2%) developed CIRD during follow-up; 21 (6.1%) were diagnosed with RA, and 16 (4.6%) with psoriatic arthritis. Longer duration of joint swelling, joint localization, and anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) positivity were independent predictors of CIRD. Six of 58 patients (10.3%) with ankle monoarthritis and 21 of 49 patients (42.9%) with wrist monoarthritis developed CIRD during follow-up. The 2010 ACR/EULAR Criteria for RA identified all patients diagnosed with seropositive RA at an early stage, mostly within 3 months. CONCLUSION: Approximately one-fourth of patients with recent-onset monoarthritis developed CIRD over 2 years. Patients presenting with ankle arthritis rarely developed CIRD, whereas patients presenting with wrist arthritis more frequently did so. Longer duration of joint swelling and ACPA and RF positivity were also predictive of CIRD. Our findings facilitate the early identification of patients with monoarthritis who have an unfavorable prognosis.
33598067 A case report of Mikulicz's disease. 2020 Mikulicz's disease is a unique condition involving the enlargement of the lacrimal and salivary glands, similar to that observed in Sjogren's syndrome; however, Mikulicz's disease is clinically characterized by infrequent autoimmune reactions and responsiveness to glucocorticoid treatment. The ultrasound features of the lacrimal and salivary glands in patients with IgG4-Mikulicz's disease were characterized by multiple hypoechoic areas of varying sizes within the enlarged glands. IgG4 serum level was also elevated, in contrast to the detection of normal levels in Sjogren's syndrome. In this article, we intended to illustrate a case of Mikulicz's disease with clinical and imaging features.
33277889 Implementing disruptive technological change in UK healthcare: exploring development of a 2020 Dec 8 PURPOSE: Developing technological innovations in healthcare is made complex and difficult due to effects upon the practices of professional, managerial and other stakeholders. Drawing upon the concept of boundary object, this paper explores the challenges of achieving effective collaboration in the development and use of a novel healthcare innovation in the English healthcare system. DESIGN/METHODOLOGY/APPROACH: A case study is presented of the development and implementation of a smart phone application (app) for use by rheumatoid arthritis patients. Over a two-year period (2015-2017), qualitative data from recorded clinical consultations (n = 17), semi-structured interviews (n = 63) and two focus groups (n = 13) were obtained from participants involved in the app's development and use (clinicians, patients, researchers, practitioners, IT specialists and managers). FINDINGS: The case focuses on the use of the app and its outputs as a system of inter-connected boundary objects. The analysis highlights the challenges overcome in the innovation's development and how knowledge sharing between patients and clinicians was enhanced, altering the nature of the clinical consultation. It also shows how conditions surrounding the innovation both enabled its development and inhibited its wider scale-up. ORIGINALITY/VALUE: By recognizing that technological artefacts can simultaneously enable and inhibit collaboration, this paper highlights the need to overcome tensions between the transformative capability of such healthcare innovations and the inhibiting effects simultaneously created on change at a wider system level.
33252847 Protocols for Experimental Sjögren's Syndrome. 2020 Dec Sjögren's syndrome (SS) is a systemic autoimmune disease affecting multiple organ systems. Salivary and lacrimal gland involvement cause dry mouth and dry eye and are the most common clinical presentations of the disease. Patients with SS also have autoantibodies targeting multiple nuclear and cytoplasmic antigens. Innate immune activation plays a critical role in SS pathogenesis. This article describes the activation of specific innate immune pathways in mice to study SS salivary gland manifestations. Methodologies for evaluating salivary gland inflammation and salivary function are described. This article also describes protocols for in-house assays to measure autoantibody titers in serum. © 2020 Wiley Periodicals LLC Basic Protocol 1: Acceleration of Sjögren's syndrome by activating the toll-like receptor 3 pathway Basic Protocol 2: Induction of Sjögren's syndrome by activating the stimulator of interferon genes pathway Alternate Protocol: Acceleration of Sjögren's syndrome by the administration of Freund's incomplete adjuvant Support Protocol 1: Evaluating salivary gland function Support Protocol 2: Evaluating salivary gland inflammation Support Protocol 3: Measuring autoantibody titers by indirect immunofluorescence.
32881039 Neonatal lupus erythematosus exacerbated by vaccination. 2020 Dec Neonatal lupus erythematosus (LE) is a rare immune-mediated disease caused by placental transport of maternal anti-SSA/Ro, anti-SSB/La and/or anti-U1RNP antibodies. Here, we demonstrate two cases of neonatal LE, in both of which cutaneous LE was exacerbated by inoculation. To our knowledge, cases worsening neonatal LE after administration of vaccines have not been reported. In case 1, not only exacerbation of pre-existing annular erythema but also spreading of new erythematous lesions to the trunk and extremities were induced following vaccination. Of interest, all of the lesions simultaneously improved. By contrast, in case 2, pre-existing facial erythema became prominent without spreading to other sites. The mother of case 1 had Sjögren's syndrome, whereas in case 2, the mother was diagnosed with Sjögren's syndrome on this occasion for the first time. Immunohistochemistry in case 1 revealed interleukin (IL)-17-positive cells infiltrating into the papillary dermis, and CD123-positive plasmacytoid dendritic cells in the papillary dermis and the deep reticular dermis. Both innate immune response and IL-17 mediated inflammation following vaccination are speculated as a possible mechanism of the deterioration of LE lesions in our juvenile cases. Caution is necessary since neonatal LE can be worsened following vaccination.
31900884 Risk of obstructive sleep apnea in patients with Sjögren syndrome and Behçet's disease: 2020 Sep PURPOSE: Patients with obstructive sleep apnea (OSA) have a higher risk of Behçet's disease (BD) and Sjögren syndrome (SS). However, the bidirectional relationship between these autoimmune diseases and OSA is unclear. We investigated the relationship between autoimmune diseases (SS and BD) and OSA. METHODS: SS and BD patients were identified through the Taiwan National Health Insurance Research Database from 2002 to 2012. Patients with SS or BD were matched according to age and sex with a control group in a ratio of 1:4. The study included 12,926 patients with SS and 51,704 non-SS controls. Similarly, 1221 patients with BD were matched with 4884 non-BD controls. We used a Cox regression model, stratified by age, gender, and comorbidities, to assess the risk of OSA. RESULTS: OSA was diagnosed in 0.61% of the SS cohort and 1.23% of the BD cohort. The higher overall risk for OSA was observed significantly in patients with SS than in controls (adjusted hazard ratio [HR] = 2.48, 95% confidence interval [CI] = 1.89-3.24). The higher risk was also observed significantly in BD patients than in controls (HR = 1.99, 95% CI = 1.06-3.72). Furthermore, men with SS or BD exhibited HR of 2.62 (95% CI 1.89 to 3.62) and 6.40 (95% CI 2.96 to 13.84) for developing OSA, respectively. CONCLUSION: Risk of OSA was significantly elevated in SS or BD patients compared with controls. Further study is warranted to elucidate underlying mechanisms.
32067777 Randomised trial on performance, safety and clinical benefit of hyaluronic acid, hyaluroni 2020 Jun OBJECTIVE: Limited data exist on the clinical benefits of nasal applications for moistening the nasal mucosa. We therefore investigated the effects of hyaluronic acid, hyaluronic acid plus dexpanthenol and isotonic saline nasal sprays in patients suffering from dry nose symptoms in an otorhinolaryngological outpatient setting. METHODS: 240 patients were randomised into this prospective, three-armed clinical trial with two assessment points (baseline and 4 weeks later). Patients received either hyaluronic acid, hyaluronic acid plus dexpanthenol or isotonic saline nasal spray over a period of four weeks. Rhinitis Sicca Symptom Score (RSSS) was assessed as primary endpoint, and individual symptoms and tolerability of all treatments as secondary endpoints. Patient perceptions after first application of the allocated nasal spray were recorded using the Nasal Spray Sensory Scale. Treatment effects were analysed for each study arm first and subsequently compared against each other. RESULTS: RSSS (hyaluronic acid: mean difference = 8.90 [98.33% CI = 7.34/10.45]; hyaluronic acid plus dexpanthenol: mean difference = 8.42 [98.33% CI = 6.91/9.94]; isotonic saline: mean difference = 8.94 [98.33% CI = 7.33/10.54]), individual symptoms and Endoscopy Score improved significantly (p < 0.001) in all treatment arms. Tolerability was assessed as "flawless" in more than 85% of all treatments, which is reflected in overall high rankings in the Nasal Spray Sensory Scale. Perception of nasal moisturisation was reported to be significantly higher in patients receiving hyaluronic acid plus dexpanthenol as compared to patients receiving hyaluronic acid or isotonic saline. No further significant differences were observed between the three treatments. CONCLUSION: All three tested sprays (hyaluronic acid, hyaluronic acid plus dexpanthenol and isotonic saline) proved to be suitable treatments for patients suffering from dry nose symptoms. (DRKS-ID: DRKS00013357).
32613869 Iguratimod treatment reduces disease activity in early primary Sjögren's syndrome: An ope 2021 Mar OBJECTIVES: To evaluate the efficacy and safety of iguratimod in patients with early primary Sjögren's syndrome (pSS). METHODS: Twenty-seven disease-modifying antirheumatic drug-naive female patients met the revised American-European Consensus Group criteria for pSS were enrolled in this open-label pilot study. Patients were treated with iguratimod 25 mg twice a day for 24 weeks. The disease activity was assessed with European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at 12 and 24 weeks. Salivary and lacrimal gland function, laboratory, and subjective variables were also assessed. Generalized estimating equations were used to analyze parameters over time. RESULTS: ESSDAI (median, 5 versus 2 versus 2, p < .01), IgG (median, 26.6 versus 22.4 versus 21.4 g/L, p < .01) and rheumatoid factor (median, 119.9 versus 94.1 versus 83.8 lU/mL, p < .01) levels decreased significantly during iguratimod treatment. ESSPRI, salivary and lacrimal gland function, fatigue and health-related quality of life did not change during treatment. One patient experienced thrombocytopenia, and no other serious adverse effects were observed. CONCLUSION: In this study, iguratimod treatment is safe and effective for improving disease activity and laboratory parameters in early pSS patients.
32167250 [Targeted therapies for connective tissue diseases and vasculitis]. 2020 Mar 11 Targeted therapies are nowadays commonly used in connective tissue diseases and vasculitis. Experts recommend the use of belimumab and rituximab in refractory and/or severe cases of lupus. Rituximab can be also considered in difficult to treat cases of Sjögren's disease or myositis. Nintedanib seems a very promising weapon in the management of systemic sclerosis-associated pulmonary fibrosis. Regarding vasculitis, rituximab has become the preferred treatment for granulomatosis with polyangiitis and microscopic polyangiitis. Finally, tocilizumab is recommended as a steroid-sparing agent in giant cell arteritis. Further clinical trials are warranted to study the efficacy of other targeted therapies in connective tissue diseases and vasculitis.
31899535 Comparative Assessment of the New PDE7 Inhibitor - GRMS-55 and Lisofylline in Animal Model 2020 Jan 2 PURPOSE: This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. METHODS: Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. RESULTS: GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC(50) of 1.06 and 0.26 mg/L, while (±)-LSF with IC(50) of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. CONCLUSIONS: PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.
32256633 Wang-Bi Capsule Alleviates the Joint Inflammation and Bone Destruction in Mice with Collag 2020 Wang-Bi Capsule (WB), a traditional Chinese medicine- (TCM-) based herbal formula, is currently used in clinic for the treatment of rheumatoid arthritis (RA) with positive clinical effects. However, its pharmacological mechanism of action in RA is still obscure. Therefore, this study established a collagen-induced arthritis (CIA) mice model to examine the efficacy of WB by using arthritis score, histological analysis, and micro-CT examination. Proinflammatory cytokines expression, osteoclast number, OPG/RANKL system, and NF-κB activation were then detected to further investigate the mechanism of WB in RA treatment. The results indicated that WB could alleviate the erythema and swelling of paws in CIA mice. It also inhibited the infiltration of inflammatory cells and bone destruction and increased bone density in joints of CIA mice. Mechanistic studies showed that WB treatment decreased the production of IL-1β, IL-6, and TNF-α in serum and joints of CIA mice. Moreover, it reduced the osteoclast number, increased OPG level, decreased RANKL level, and inhibited the activation of NF-κB in joints of CIA mice. In conclusion, this study demonstrated that WB could effectively alleviate disease progression of CIA mice by decreasing the IL-1β, IL-6, and TNF-α levels, modulating the OPG/RANKL system, and inhibiting the activation of NF-κB.
32912276 Tocilizumab may slow radiographic progression in patients with systemic or polyarticular-c 2020 Sep 10 BACKGROUND: Few clinical trials have investigated the prevention of radiographic progression in children with juvenile idiopathic arthritis treated with antirheumatic drugs. This study aimed to investigate radiographic progression in patients with systemic juvenile idiopathic arthritis (sJIA) and patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with the anti-interleukin-6 receptor antibody tocilizumab for 2 years in the TENDER and CHERISH randomized controlled trials, respectively. METHODS: Standard radiographs of both wrists and both hands in the posteroanterior view were obtained within 4 weeks of baseline and were repeated at weeks 52 ± 4 and 104 ± 4 in both trials. All films were scored by two independent readers using the adapted Sharp-van der Heijde (aSH) and Poznanski scoring methods. Although the Poznanski score indicates bone growth limitation or cartilage growth decrease, which are not the same as joint space narrowing in rheumatoid arthritis, its change reflects damage to cartilage. Therefore, impairment in the Poznanski score as well as the aSH score was considered as a measure of structural joint damage. Radiographic progression was defined as worsening of radiographic scores beyond the smallest detectable difference. RESULTS: Poznanski and aSH scores were available at baseline and at one or more postbaseline time points for 33 and 47 of 112 sJIA patients and 61 and 87 of 188 pcJIA patients, respectively, providing a representative subset of the study populations. The inter-reader and intra-reader agreement intra-class correlation coefficient was > 0.8. Median baseline Poznanski and aSH scores, respectively, were - 2.4 and 24.6 for sJIA patients and - 1.5 and 8.0 for pcJIA patients. Compared with baseline, aSH scores remained stable for all sJIA patients at week 52, whereas 9.4% of sJIA patients had radiographic progression according to Poznanski scores at week 52; at 104 weeks, radiographic progression according to aSH and Poznanski scores was observed in 5.4% and 11.5%, respectively. In pcJIA patients, radiographic progression from baseline at 52 weeks and at 104 weeks was 12.5% and 2.9%, respectively, using aSH scoring and 6.5% and 4%, respectively, using Poznanski scoring. CONCLUSION: Tocilizumab may delay radiographic progression in children with sJIA and children with pcJIA. TRIAL REGISTRATION: Trial registration numbers and dates: TENDER, NCT00642460 (March 19, 2008); CHERISH, NCT00988221 (October 1, 2009).
32817415 IL-12 p40 monomer is different from other IL-12 family members to selectively inhibit IL-1 2020 Sep 1 Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system. The IL-12 family of cytokines has four members, which are IL-12 (p40:p35), IL-23 (p40:p19), the p40 monomer (p40), and the p40 homodimer (p40(2)). Since all four members contain p40 in different forms, it is important to use a specific monoclonal antibody (mAb) to characterize these molecules. Here, by using such mAbs, we describe selective loss of p40 in serum of MS patients as compared to healthy controls. Similarly, we also observed decrease in p40 and increase in IL-12, IL-23, and p40(2) in serum of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as compared to control mice. Interestingly, weekly supplementation of mouse and human recombinant p40 ameliorated clinical symptoms and disease progression of EAE. On the other hand, IL-12, IL-23, and p40(2) did not exhibit such inhibitory effect. In addition to EAE, p40 also suppressed collagen-induced arthritis in mice. Using IL-12Rβ1(-/-), IL-12Rβ2(-/-), and IL-12Rβ1(+/-)/IL-12Rβ2(-/-) mice, we observed that p40 required IL-12Rβ1, but not IL-12Rβ2, to suppress EAE. Interestingly, p40 arrested IL-12-, IL-23-, or p40(2)-mediated internalization of IL-12Rβ1, but neither IL-12Rβ2 nor IL-23R, protected regulatory T cells, and suppressed Th1 and Th17 biasness. These studies identify p40 as an anti-autoimmune cytokine with a biological role different from IL-12, IL-23, and p40(2) in which it attenuates autoimmune signaling via suppression of IL-12Rβ1 internalization, which may be beneficial in patients with MS and other autoimmune disorders.
33149772 The off-label use of anakinra in pediatric systemic autoinflammatory diseases. 2020 Interleukin 1 (IL-1), a central mediator of innate immunity, is considered a master cytokine of local and systemic inflammation. IL-1 has emerged as pivotal in the pathogenesis of autoinflammatory diseases (AIDs), and blockade of its pathway has become a crucial target for therapy. Anakinra (ANA), a recombinant IL-1β receptor antagonist, was the first anti-IL-1 agent employed in clinical practice. ANA is currently approved for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and cryopyrin-associated autoinflammatory syndrome. It has also been successfully used for off-label treatment of various monogenic, polygenic, or undefined etiology systemic AIDs. This review describes currently available evidence for the off-label use of ANA in pediatric rheumatologic diseases. Specifically, the use of ANA in Kawasaki disease, idiopathic recurrent pericarditis, Behçet disease, monogenic AIDs, undifferentiated AIDs, chronic non-bacterial osteomyelitis, macrophage activation syndrome, and febrile infection-related epilepsy, in terms of its safety and efficacy. In selected pediatric rheumatic disorders, the off-label administration of ANA appears to be effective and safe. In order to control severe and/or relapsing disease, ANA should be considered as a valuable treatment option in children suffering from rare inflammatory diseases. However, currently available data consist of retrospective studies and short case series; thus, randomized controlled trials and larger series with long-term follow up are mandatory to better assess the efficacy and cost effectiveness of ANA in these challenging patients.
32655775 The role of indoleamine 2,3 dioxygenase 1 in the osteoarthritis. 2020 Osteoarthritis (OA) is a chronic degenerative joint disease and a leading cause of disability. It involves articular cartilage destruction and a whole joint inflammation. In spite of OA pathogenesis is still unclear, new studies on the OA pathophysiological aetiology and immunomodulation therapy continuously achieve significant advances with new concepts. Here, we focus on the indoleamine-2,3-dioxygenase1 (IDO1) activity in the osteoarthritis (OA), which is one of the noticeable enzymes in the synovial fluid of arthritis patients. It was recognized as an essential mediator of autoreactive B and T cell responses in rheumatoid arthritis (RA) and an interesting therapeutic target against RA. However, the role IDO1 plays in the OA pathogenesis hasn't been discussed. The new OA experimental analysis evidenced IDO1 overexpression in the synovial fluid of OA patients, and recent studies reported that IDO1 metabolites were found higher in the OA synovial fluid than RA and spondyloarthropathies (SpA) patients. Moreover, the positive relation of IDO1 metabolites with OA pain and joint stiffness has been confirmed. Thus, the IDO1 plays a pivotal role in the pathogenesis of OA. In this review, the role IDO1 plays in the OA pathogenesis has been deeply discussed. It could be a promising target in the immunotherapy of OA disease.
32551607 Discovery of 4,6- and 5,7-Disubstituted Isoquinoline Derivatives as a Novel Class of Prote 2020 Jul 9 Two chemical series of novel protein kinase C ζ (PKCζ) inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines, were rapidly identified using our fragment merging strategy. This methodology involves biochemical screening of a high concentration of a monosubstituted isoquinoline fragment library, then merging hit isoquinoline fragments into a single compound. Our strategy can be applied to the discovery of other challenging kinase inhibitors without protein-ligand structural information. Furthermore, our optimization effort identified the highly potent and orally available 5,7-isoquinoline 37 from the second chemical series. Compound 37 showed good efficacy in a mouse collagen-induced arthritis model. The in vivo studies suggest that PKCζ inhibition is a novel target for rheumatoid arthritis (RA) and that 5,7-disubstituted isoquinoline 37 has the potential to elucidate the biological consequences of PKCζ inhibition, specifically in terms of therapeutic intervention for RA.