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ID PMID Title PublicationDate abstract
33086170 Artesunate inhibits Sjögren's syndrome-like autoimmune responses and BAFF-induced B cell 2021 Jan BACKGROUND: Hyperactivation of B cells by activators has been demonstrated to play a central role in the pathogenesis of Sjögren's syndrome (SS). In this study, we found that artesunate (ART) can attenuate BAFF-induced B cell hyperactivation and SS-like symptoms in NOD/Ltj mice. PURPOSE: To determine the efficacy of ART in attenuating SS-like symptoms in vivo and explore the underlying mechanism in vitro. STUDY DESIGN: ART was intragastrically injected into SS-like NOD/Ltj mice. The cytokine hsBAFF was used to activate Raji and Daudi B cells to mimic B cell hyperactivation in vitro. METHODS: The efficacy of ART in inhibiting SS progression was studied in NOD/Ltj mice. Salivary flow rate, the number of lymphocytic infiltration foci, the level of autoantibodies and the extent of B cell infiltration were measured in the indicated groups. CCK-8 assays, flow cytometry-based EdU staining and Annexin V/PI staining were also used to detect the effect of ART on the survival and proliferation mechanism in BAFF-induced Raji and Daudi cells. Further studies determined that TRAF6 degradation is a potential mechanism by which ART determines B cell fate. RESULTS: Treatment with ART inhibited lymphocytic foci formation, B cell infiltration and autoantibody secretion in SS-like NOD/Ltj mice. In vitro assay results indicated that ART effectively inhibited BAFF-induced viability, survival and proliferation of neoplastic B cells. Mechanistically, ART targeted BAFF-activated NFκB by regulating the proteasome-mediated degradation of TRAF6 in Raji and Daudi cells. CONCLUSION: ART ameliorated murine SS-like symptoms and regulated TRAF6-NFκB signaling, thus determining survival and proliferation of B cells.
35610714 Coxiella burnetti prosthetic joint infection in an immunocompromised woman: iterative surg 2021 Dec 2 BACKGROUND: Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii, a strictly intracellular pathogen that can cause acute and chronic infection. Chronic Q fever can occur in immunocompetent as well as in immuno-compromised hosts, as a persistent localized infection. The main localizations are endocardial, vascular and, less frequently, osteoarticular. The most frequent osteoarticular form is spondyliscitis. Recommended treatment is combined doxycycline and hydroxychloroquine for 18 months, with cotrimoxazole as another option. Coxiella burnetti infection has been implicated in rare cases of prosthetic joint infection (PJI), and the medical and surgical management and outcome in such cases have been little reported. CASE PRESENTATION: We report an unusual case of chronic Q fever involving a hip arthroplasty in an immunocompromised woman treated with tumor necrosis factor (TNF)-α blockers for rheumatoid arthritis. Numerous surgical procedures (explantation, "second look", femoral resection and revision by megaprosthesis), modification of the immunosuppressant therapy and switch from doxycycline-hydroxychloroquine to prolonged ofloxacin-rifampin combination therapy were needed to achieve reconstruction and treat the PJI, with a follow-up of 7 years. CONCLUSIONS: Coxiella burnetti PJI is a complex infection that requires dedicated management in an experienced reference center. Combined use of ofloxacin-rifampin can be effective.
34737599 Albumin/Globulin Ratio as Yin-Yang in Rheumatoid Arthritis and Its Correlation to Inflamm- 2021 PURPOSE: Inflamm-aging is a novel-concept in rheumatoid arthritis (RA) with accelerating aging process. We try to find a correlation between serum albumin/globulin (A/G) ratio and clinical biochemical parameters, incidence of aging-related diseases (ARDs) as well as inflammaging-related molecules. PATIENTS AND METHODS: Healthy controls (HC) and RA patients were compared with their clinical biochemical parameters including albumin and globulin levels, A/G ratio, and levels of serum lipids. Incidence of ARDs in RA was compared with A/G ratio, having a cut off value of 1.2. Expression levels of leptin and Trf2 genes in PBMCs, and inflammatory factors like IL-1β, IL-6, IL-8 and TNF-ɑ between HC and RA patients were compared, and correlated with the A/G ratio. RESULTS: Compared to HC, RA patients had decreased levels of albumin, while globulin levels were found to be increased, which led to a significantly lower A/G ratio in RA patients. A/G ratio rather than ESR and CRP had significant correlation with dyslipidemia in RA patients. Patients with A/G <1.2 had a higher risk of ARDs than patients with A/G >1.2. The RR was 2.48 (95% CI: 1.79 to 3.64, p <0.0001). In addition, A/G ratio has positively correlated to leptin and Trf2 expression, while an inverse correlation was observed with the levels of inflamm-aging related cytokines like IL-6, IL-8 and TNF-ɑ. CONCLUSION: A decreased A/G ratio in RA patients has significantly correlated with dyslipidemia and ARDs, as well as inflammaging- related adipokine and pro-inflammatory cytokines. Thus, A/G ratio could be a reliable marker for evaluating the inflammaging process during clinical management in ARDs.
34560064 The Inducible Nitric Oxide Synthase Pathway Promotes Osteoclastogenesis under Hypoxic Cult 2021 Dec Bone homeostasis depends on the balance between bone resorption by osteoclasts (OCs) and bone formation by osteoblasts. Bone resorption can become excessive under various pathologic conditions, including rheumatoid arthritis. Previous studies have shown that OC formation is promoted under hypoxia. However, the precise mechanisms behind OC formation under hypoxia have not been elucidated. The present study investigated the role of inducible nitric oxide synthase (iNOS) in OC differentiation under hypoxia. Primary bone marrow cells obtained from mice were stimulated with receptor activator of NF-κB ligand and macrophage colony-stimulating factor to induce OC differentiation. The number of OCs increased in culture under hypoxia (oxygen concentration, 5%) compared with that under normoxia (oxygen concentration, 20%). iNOS gene and protein expression increased in culture under hypoxia. Addition of an iNOS inhibitor under hypoxic conditions suppressed osteoclastogenesis. Addition of a nitric oxide donor to the normoxic culture promoted osteoclastogenesis. Furthermore, insulin-like growth factor 2 expression was significantly altered in both iNOS inhibition experiments and nitric oxide donor experiments. These data might provide clues to therapies for excessive osteoclastogenesis under several hypoxic pathologic conditions, including rheumatoid arthritis.
34140814 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 2021 PURPOSE: ATI-450 is an oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) inflammatory signaling pathway. This phase 1, single and multiple ascending dose (SAD, MAD) study evaluated ATI-450 safety, tolerability, pharmacokinetics, and pharmacodynamics. PATIENTS AND METHODS: Healthy adults were randomly assigned to SAD (10, 30, 50, 100 mg; n=24) and MAD (10, 30, 50 mg twice daily [BID] for 7 days; n=24) cohorts of ATI-450 or placebo (n=14). Safety and tolerability were evaluated through clinical and laboratory assessments. Pharmacokinetic parameters were evaluated in plasma samples; pharmacodynamic assessments included quantification of cytokine levels (tumor necrosis factor α [TNF-α], interleukin [IL]-1β, IL-6, IL-8) and phosphorylation of the MK2 downstream substrate, heat shock protein 27 (p-HSP27). RESULTS: The most common adverse events were headache (10/48, 20.8%), dizziness (6/48, 12.5%), upper respiratory tract infection (3/48, 6.3%), and constipation (3/48, 6.3%). Pharmacokinetics were dose-proportional, with a terminal half-life of 9‒12 hours in the MAD cohorts on day 7. Dose- and concentration-dependent inhibition of ex vivo stimulated cytokines and target biomarker was observed. On day 7, patients in the 50 mg BID dose cohort recorded mean trough drug levels that were 1.4, 2.2, 2.3, and 2.4 times greater than the IC(80) for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. Mean C(max) was 3.5, 5.4, 5.6, and 6.0 times greater than the IC(80) for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. IL-6 inhibition >50% was noted for part of the dosing interval. CONCLUSION: ATI-450 was well tolerated at the doses investigated, exhibited dose- and time-independent (ie, linear) pharmacokinetics, and dose-related pharmacodynamic effects. These results support further study of ATI-450 in immunoinflammatory diseases in phase 2 trials.
33609083 Perspectives of Glucocorticoid Use in Patients with Rheumatoid Arthritis. 2021 Apr OBJECTIVE: Prednisolone is an effective oral glucocorticoid for managing symptoms of rheumatoid arthritis (RA) but has predictable and common adverse effects. We explored patient perspectives of prednisolone use in RA. METHODS: Patients with RA registered with the Australian Rheumatology Association Database (ARAD) who had completed an ARAD questionnaire in the preceding 12 months were invited to participate in an online survey. Responses were linked to already collected respondent demographics, medication use, and patient-reported outcome measures. The Beliefs about Medicine Questionnaire (BMQ) measured patient beliefs on medication necessity and concerns. Free-text responses outlining reasons for stopping or declining prednisolone underwent thematic analysis using NVivo 12. RESULTS: The survey response rate was 79.6% (804/1010), including 251 (31.2%) reporting current prednisolone use and 432 (53.7%) reporting previous use. Compared with previous users, current users were older (P = 0.0002) and had worse self-reported pain, disease activity, health-related quality of life, and function (all P < 0.001). Current users had higher BMQ scores for prednisolone-specific necessity (3.6 versus 1.7; P <0.001) and concerns (2.7 versus 2.3; P <0.001). In previous prednisolone users (n = 432), the most frequent themes identified in free-text responses for cessation were adequate disease control (30.3%), adverse effects (25.2%), and predetermined short courses (21.3%). Of respondents citing adverse effects for cessation (n = 131), weight gain (27.5%), osteoporosis (14.7%), and neuropsychiatric issues (13.8%) were most frequent. CONCLUSIONS: In our cohort, patients with RA taking prednisolone believed it was necessary yet remained concerned about its use. Adequate disease control and adverse effects were important considerations for patients using prednisolone.
34545472 Patient-Reported Care Coordination is Associated with Better Performance on Clinical Care 2021 Dec BACKGROUND: Prior studies using aggregated data suggest that better care coordination is associated with higher performance on measures of clinical care process; it is unclear whether this relationship reflects care coordination activities of health plans or physician practices. OBJECTIVE: Estimate within-plan relationships between beneficiary-reported care coordination measures and HEDIS measures of clinical process for the same individuals. DESIGN: Mixed-effect regression models in cross-sectional data. PARTICIPANTS: 2013 Medicare Advantage CAHPS respondents (n=152,069) with care coordination items linked to independently collected HEDIS data on clinical processes. MAIN MEASURES: Care coordination measures assessed follow-up, whether doctors had medical records during visits, whether doctors discussed medicines being taken, how informed doctors seemed about specialist care, and help received with managing care among different providers. HEDIS measures included mammography, colorectal cancer screening, cardiovascular LDL-C screening, controlling blood pressure, 5 diabetes care measures (LDL-C screening, retinal eye exam, nephropathy, blood sugar/HbA1c <9%, LCL-C<100 mg/dL), glaucoma screening in older adults, BMI assessment, osteoporosis management for women with a fracture, and rheumatoid arthritis therapy. KEY RESULTS: For 9 of the 13 HEDIS measures, within health plans, beneficiaries who reported better care coordination also received better clinical care (p<0.05) and none of the associations went in the opposite direction; HEDIS differences between those with excellent and poor coordination exceeded 5 percentage points for 7 measures. Nine measures had positive associations (breast cancer screening, colorectal cancer screening, cardiovascular care LDL-C screening, 4 of 5 diabetes care measures, osteoporosis management, and rheumatoid arthritis therapy). CONCLUSIONS: Within health plans, beneficiaries who report better care coordination also received higher-quality clinical care, particularly for care processes that entail organizing patient care activities and sharing information among different healthcare providers. These results extend prior research showing that health plans with better beneficiary-reported care coordination achieved higher HEDIS performance scores.
34474172 Response to SARS-CoV-2 vaccination in immune mediated inflammatory diseases: Systematic re 2022 Jan OBJECTIVES: The treatment for COVID-19 often utilizes immune-modulating drugs. These drugs are also used in immune mediated inflammatory diseases (IMIDs). We performed a systematic review about seroconversion after SARS-CoV-2 vaccination in patients with IMIDs and impact of various drugs on seroconversion rates. METHODS: Electronic databases were searched to identify relevant studies reporting seroconversion rates following SARS-CoV-2 vaccination in IMIDs. We calculated the pooled seroconversion rates after a single or two doses of vaccination, pooled seroconversion rates in patients with specific IMIDs, and rates in patients on various drugs/drug classes. RESULTS: Twenty-five studies were included in the systematic review. The pooled seroconversion rates after two doses of mRNA vaccination were higher (83.1, 95%CI: 74.9-89.0, I(2) = 90%) as compared to a single dose (69.3, 52.4-82.3, I(2) = 95%). The odds of seroconversion were lower in IMIDs as compared to healthy controls (0.05, 0.02-0.13, I(2) = 21%). The seroconversion rates in patients with inflammatory bowel disease (95.2, 95%CI: 92.6-96.9, I(2) = 0%), spondyloarthropathy (95.6, 95% CI: 83.4-98.9, I(2) = 35%), and systemic lupus erythematosus (90.7, 95%CI: 85.4-94.2, I(2) = 0%) were higher as compared to rheumatoid arthritis (79.5, 95% CI: 65.1-88.9, I(2) = 85%), and vasculitis (70.5, 95% CI: 52.9-83.5, I(2) = 51%). The seroconversion rates following double dose of mRNA were excellent (>90%) in those on anti-tumour necrosis factor (TNF), anti-integrin (vedolizumab), anti-IL 17 (secukinumab), anti-IL6 (Tocilizumab) and anti-IL12/23 (Ustekinumab) therapies but attenuated (<70%) in patients on anti-CD20 (Rituximab) or anti-cytotoxic T lymphocyte associated antigen (CTLA-4) therapies (Abatacept). The seroconversion rates were good (70-90%) with steroids, hydroxychloroquine, JAK inhibitors, mycophenolate mofetil and leflunomide. Combination of anti-TNF with immunomodulators (azathioprine, 6-meracptopurine, methotrexate) resulted in an attenuated vaccine response as compared to anti-TNF monotherapy. CONCLUSION: Seroconversion rates after SARS-CoV-2 vaccination are lower in patients with IMIDs. Certain therapies (anti-TNF, anti-integrin, anti-IL 17, anti-IL6, anti-12/23) do not impact seroconversion rates while others (anti-CD20, anti-CTLA-4) result in poorer responses.
33884000 Potency of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin in Complete Freund' 2021 Rheumatoid arthritis (RA) is an autoimmune syndrome affecting joint spaces, leading to the disabled state. Currently, there is no optimal therapy for RA except for systemic immunosuppressants that have variable undesirable effects after long-term use. Hence, the need for other treatment modalities has emerged in an attempt to develop a treating agent that is effective but without bad effects. Bone marrow-derived mesenchymal stem cells (BM-MSCs) may be an alternative medicine since they may differentiate into a variety of mesenchymal tissues including bone and cartilage. Indomethacin (IMC) could be suggested as an analgesic, anti-inflammatory, and antirheumatic potential agent against the course of RA since it possesses significant palliative effects and antipyretic properties. Therefore, our target of this study was to explore and compare the effect of BM-MSCs (1 × 10(6) cells/rat at the 1(st), 6(th), 12(th), and 18(th) days) and IMC (2 mg/kg b.w./day for 3 weeks) either alone or in combination on arthritic rats. The model of rheumatoid arthritis in rats was induced by subcutaneous injection of 0.1 mL/rat CFA into the footpad of the right hind paw. The BM-MSC intravenous injection and IMC oral administration significantly reduced the elevated right hind leg paw diameter and circumference, serum anti-CCP, and ankle joint articular tissue expressions of TNF-α, iNOS, MMP-9, and TGF-β1 while they significantly increased the lowered articular IL-10 expression in CFA-induced arthritic rats. The combinatory effect of the two treatments was the most potent. In conclusion, the treatment of RA with BM-MSCs and IMC together is more effective than the treatment with either BM-MSCs or IMC. The Th1 cytokine (TNF-α), Th2 cytokine (IL-10), iNOS, MMP-9, and TGF-β1 are important targets for mediating the antiarthritic effects of BM-MSCs and IMC in CFA-induced arthritis in rats.
34474649 Effect of initiating biologics compared to intensifying conventional DMARDs on clinical an 2021 Sep 2 Objectives: To compare the effect of treat-to-target-based escalations in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics on clinical disease activity and magnetic resonance imaging (MRI) inflammation in a rheumatoid arthritis (RA) cohort in clinical remission.Method: One-hundred patients with established RA, Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP) < 3.2, and no swollen joints (hereafter referred to as 'in clinical remission') who received csDMARDs underwent clinical evaluation and MRI of the wrist and second to fifth metacarpophalangeal joints every 4 months. They followed a 2 year MRI treatment strategy targeting DAS28-CRP ≤ 3.2, no swollen joints, and absence of MRI osteitis, with predefined algorithmic treatment escalation: first: increase in csDMARDs; second: adding a biologic; third: switch biologic. MRI osteitis and Health Assessment Questionnaire (HAQ) (co-primary outcomes) and MRI combined inflammation and Simplified Disease Activity Index (SDAI) (key secondary outcomes) were assessed 4 months after treatment change and expressed as estimates of group differences. Statistical analyses were based on the intention-to-treat population analysed using repeated-measures mixed models.Escalation to first biologic compared to csDMARD escalation more effectively reduced MRI osteitis (difference between least squares means 1.8, 95% confidence interval 1.0-2.6), HAQ score (0.08, 0.03-0.1), MRI combined inflammation (2.5, 0.9-4.1), and SDAI scores (2.7, 1.9-3.5).Treat-to-target-based treatment escalations to biologics compared to escalation in csDMARDs more effectively improved MRI inflammation, physical function, and clinical disease activity in patients with established RA in clinical remission. Treatment escalation in RA patients in clinical remission reduces clinical and MRI-assessed disease activity.Trial registration: Clinicaltrials.gov identifier: NCT01656278.
34234773 The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activat 2021 The myeloid inhibitory C-type lectin receptor CLEC12A limits neutrophil activation, pro-inflammatory pathways and disease in mouse models of inflammatory arthritis by a molecular mechanism that remains poorly understood. We addressed how CLEC12A-mediated inhibitory signaling counteracts activating signaling by cross-linking CLEC12A in human neutrophils. CLEC12A cross-linking induced its translocation to flotillin-rich membrane domains where its ITIM was phosphorylated in a Src-dependent manner. Phosphoproteomic analysis identified candidate signaling molecules regulated by CLEC12A that include MAPKs, phosphoinositol kinases and members of the JAK-STAT pathway. Stimulating neutrophils with uric acid crystals, the etiological agent of gout, drove the hyperphosphorylation of p38 and Akt. Ultimately, one of the pathways through which CLEC12A regulates uric acid crystal-stimulated release of IL-8 by neutrophils is through a p38/PI3K-Akt signaling pathway. In summary this work defines early molecular events that underpin CLEC12A signaling in human neutrophils to modulate cytokine synthesis. Targeting this pathway could be useful therapeutically to dampen inflammation.
34728318 SZAP exerts analgesic effects on rheumatalgia in CIA rats by suppressing pain hyperalgesia 2022 Feb 10 ETHNOPHARMACOLOGICAL RELEVANCE: ShexiangZhuifeng Analgesic Plaster (SZAP) is a traditional Chinese medicine and transdermal formulation composed of many Chinese herbs and active compounds. SZAP was recently approved by the China Food and Drug Administration for the treatment of pain associated with osteoarticular diseases and is preferred by most rheumatoid arthritis patients in China. However, its mechanism has not been elucidated in detail. AIM OF THE STUDY: We sought to determine the analgesic effect of SZAP in collagen-induced arthritis (CIA) rats and explore the underlying mechanisms of pain transmission, such as via the TRPV1 and P2X3 receptors. METHODS: After CIA was established, rats were treated with SZAP for 7 days. Paw thickness, arthritis score, and haematoxylin and eosin staining were used to evaluate the effectiveness of SZAP. Paw withdrawal threshold (PWT) and tail-flick latency (TFL) were used to estimate the analgesic effect of SZAP. The levels of PGE(2), BK, 5-HT, SP, and CGRP in the serum and synovium were determined using ELISA kits, and ATP in the synovium was measured using HPLC. The expression of TRPV1 and P2X3 in the DRG was detected using western blotting and immunofluorescence. TRPV1 and P2X3 agonists were further used to determine the analgesic effects of SZAP on CIA rats based on PWT and TFL. RESULTS: SZAP not only significantly ameliorated arthritis scores and paw thickness by improving the pathological damage of synovial joints, but also remarkably alleviated pain in CIA rats. Further, treatment with SZAP significantly reduced peripheral 5-HT, PGE(2) BK, SP, CGRP, and ATP. Additionally, the expression of TRPV1 and P2X3 in the DRG was markedly downregulated by SZAP. Interestingly, the analgesic effect of SZAP was weakened (reduction of PWT and TFL) when TRPV1 and P2X3 were activated by capsaicin or α,β-meATP, respectively. CONCLUSION: SZAP ameliorates rheumatalgia by suppressing hyperalgesia and pain transmission through the inhibition of TRPV1 and P2X3 in the DRG of CIA rats.
33985537 Soufeng sanjie formula alleviates collagen-induced arthritis in mice by inhibiting Th17 ce 2021 May 13 BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch), scorpion (dried body of Buthus martensii Karsch), astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge), and black soybean seed coats (seed coats of Glycine max (L.) Merr), is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remains unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice. METHODS: For in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/day) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 days, degree of ankle joint destruction and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Moreover, the expression levels of retinoic acid receptor-related orphan nuclear receptor (ROR) γt and phosphorylated STAT3 (pSTAT3, Tyr705) in the spleen were detected by immunohistochemistry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in CD4(+) T cells under Th17 polarization conditions. RESULTS: SF decreased the arthritis score, ameliorated paw swelling, and reduced cartilage loss in the joint of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG in sera of CIA mice. SF decreased the levels of inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 both in the sera and the joint of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. SF also reduced the expression levels of ROR γt and pSTAT3 (Tyr705) in the spleen of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, IL-17A, and pSTAT3 (Tyr705) under Th17 polarization conditions. CONCLUSIONS: Our results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.
34031570 Juvenile idiopathic arthritis: lymphocyte activation gene-3 is a central immune receptor i 2021 Oct BACKGROUND: We investigated the role of inhibitory receptors (IRs) and especially lymphocyte activation gene-3 (LAG-3) in the pathogenesis of oligoarticular juvenile idiopathic arthritis (o-JIA). METHODS: Paired samples of synovial fluid (SF) and plasma and peripheral blood (PBMCs) and synovial fluid mononuclear cells (SFMCs) were collected from o-JIA patients along with their clinical data (n = 24). Plasma from healthy controls (n = 14) and paired SF and plasma samples from five non-arthritic juvenile orthopedic patients (n = 5) served as controls. Spontaneously differentiated fibroblast-like synoviocytes (FLSs) from SFMCs were co-cultured with autologous PBMCs/SFMCs and used as ex vivo disease model. Soluble levels and cellular expressions of IRs together with their functional properties in the ex vivo model were analyzed. RESULTS: In patients with o-JIA, soluble levels of LAG-3 and expression of LAG-3 and T cell immunoglobulin mucin03 (TIM-3) on CD3(+)CD4(+)CD45RO(+) T cells were increased, especially in SF. Major histocompatibility complex (MHC) class II expression was induced on FLSs when these were co-cultured with autologous PBMCs/SFMCs, together with an increased monocyte chemoattractant protein-1 (MCP-1) production. In PBMC and FLS + PBMC co-cultures, neutralizing antibodies to IRs were added. Only anti-LAG-3 antibodies significantly increased MCP-1 secretion. The addition of agonistic LAG-3 antibody resulted in decreased effector cytokine secretion. CONCLUSIONS: This is the first report comparing the effects of different IRs in o-JIA and suggests that LAG-3 might contribute to the pathogenesis of this disease. IMPACT: This is the first study addressing the role of different co-IRs in o-JIA. We showed that LAG-3 and TIM-3 seem more important in juvenile arthritis in contrast to adult rheumatoid arthritis, where cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death-1 were reported to be more important. We designed an ex vivo disease model for o-JIA, examined the effects of co-IRs in this model, and demonstrated that they might contribute to the pathogenesis of the disease. LAG-3 might play a role in o-JIA pathogenesis and might be a potential therapeutic option for o-JIA patients.
33751358 A Dual Target-Directed Single Domain-Based Fusion Protein Against Interleukin-6 Receptor D 2021 Aug The currently used anti-cytokine therapeutic antibodies cannot selectively neutralize pathogenic cytokine signalling that cause collateral damage to protective signalling cascades. The single domain chain firstly discovered in Camelidae displays fully functional ability in antigen-binding against variable targets, which has been seemed as attractive candidates for the next-generation biologic drug study. In this study, we established a simple prokaryotic expression system for a dual target-directed single domain-based fusion protein against the interleukin-6 receptor and human serum, albumin, the recombinant anti-IL-6R fusion protein (VHH-0031). VHH-0031 exhibited potent anti-inflammatory effects produced by LPS on cell RAW264.7, where the major cytokines and NO production were downregulated after 24 h incubation with VHH-0031 in a dose-dependent manner. In vivo, VHH-0031 presented significant effects on the degree reduction of joint swelling in the adjuvant-induced arthritis (AIA) rat, having a healthier appearance compared with the dexamethasone. The expression level of JNK protein in the VHH-0031 group was significantly decreased, demonstrating that VHH-0031 provides a low-cost and desirable effect in the treatment of more widely patients.
33795495 Temporomandibular joint involvement in children with juvenile idiopathic arthritis: A sing 2021 Apr OBJECTIVES: To describe the clinical and laboratory characteristic, state the treatment and outcome of patients with juvenile idiopathic arthritis (JIA), and describe temporomandibular joint (TMJ) involvement as observed in a large tertiary center. METHODS: A retrospective cross-sectional study of children diagnosed with JIA was assessed at King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia (2015-2019), which included a descriptive analysis of children who had TMJ involvement among our study group. Subjects diagnosed with the TMJ arthritis were based either on clinical musculoskeletal examination or using contrast-enhanced MRI. RESULTS: We reviewed 123 cases with different JIA subtypes (57% females). The most frequent subtype is the oligoarticular (36%). TMJ involvement was found in 16% (n=20/123) of the patients, of whom 45% had Polyarticular JIA. The rheumatoid factor was positive in 25%; antinuclear antibody (ANA) in 45% and none showed positivity to HLAB27. Treatment resulted in complete resolution in 95% of cases, while Micrognathia and obstructive sleep apnea were the complications reported in 5% of cases. CONCLUSION: TMJ involvement in JIA is not uncommon. Females with polyarticular disease were more frequently affected with TMJ arthritis. Positive ANA could be a risk factor for TMJ involvement, while positive HLAB27 might have some protective effects. Early treatment for TMJ arthritis is essential to avoid possible complications.
35382362 Patient perspectives on biological treatments for inflammatory arthritis: A multi-center s 2021 Dec OBJECTIVES: The aim of this study was to evaluate the patient's perception of the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) and provide a basis for physicians to understand the patient's perspective. PATIENTS AND METHODS: Between December 2018 and June 2019, a total of 307 patients (162 males, 145 females; mean age: 48 years; range, 18 to 81 years) were included in this investigator-initiated, multi-center, observational, and cross-sectional study in six rheumatology centers. We asked patients using bDMARDs to treat rheumatoid arthritis (RA) or ankylosing spondylitis (AS) to complete a questionnaire regarding major considerations and satisfaction with bDMARDs, preferred administration route, knowledge about bDMARDs, experiences of adverse events, non-adherence, and expectations of their healthcare provider. The satisfaction of physician and clinical information on the patient's disease and treatment were also collected. RESULTS: Of the patients, 139 had RA and 168 had AS. Median disease duration was six years in RA and five years in AS. A total of 80.1% of the patients and 77.1% of the physicians indicated being satisfied or very satisfied with the therapeutic effect of the current bDMARD. Most patients were open to intravenous or subcutaneous injection, with the most preferred route of administration being subcutaneous (41.3%), followed by intravenous (32.0%), and oral (26.7%). The patients considered therapeutic effect to be more important than cost or convenience while choosing a bDMARD (69.3%), and most were willing to be educated about therapeutic effects (46.1%). Only 35.2% of the patients reported well and/or very well knowledge about the therapeutic effects, side effects, and administration methods of their current bDMARD, and 86.6% cited their physician as the primary source of information about biological treatment. CONCLUSION: Patients value therapeutic effect more than cost or convenience while selecting a bDMARD, and consider their physicians to be the primary information source. Therefore, it is important for physicians to provide appropriate education and encourage patients to cooperate actively with treatment.
34543280 Prevalence and relevant factors of positive RF in brucellosis patients with arthralgia. 2021 Sep BACKGROUND: Brucellosis is a critical zoonotic disease in the world, it is the non-specific arthralgia that make brucellosis patients easily misdiagnosed as rheumatoid arthritis (RA) in endemic regions. Elevated rheumatoid factor (RF) is an essential indicator of RA, and the RF in brucellosis patients is significantly higher than healthy people. Therefore, this study further explored the distribution of RF and the relevant factors of the RF positivity in brucellosis patients with arthralgia, in order to strengthen the recognition of physicians for brucellosis patients with RF positivity, especially in brucellosis-endemic areas, so as to avoid misdiagnosis and untimely treatment that may lead to malignant outcomes. METHODOLOGY AND PRINCIPAL FINDINGS: The medical records of all 572 brucellosis inpatients were collected in the Sixth People's Hospital of Shenyang, China from 2015 to 2016. After excluding 106 patients without arthralgia, 5 patients who unwilling to perform RF testing and 16 patients with diseases that may affect RF, 445 brucellosis inpatients with arthralgia were involved in this retrospective cross-sectional study. 143 (32.1%) patients with RF >10 IU/ml were classified into the RF positive group, with an average level of 16.5[12.2, 34.7] IU/ml, of which 45 (10.1%) patients were high-positive with RF >30 IU/ml. Multivariate logistic regression model was used to further analyze the relevant factors of the RF positivity and found that age, wrist joint pain and elevated C-reactive protein (CRP) were positively associated with RF positivity, with OR of 1.02 (P = 0.024), 8.94 (P = 0.008) and 1.79 (P = 0.019), respectively. CONCLUSION: The prevalence of positive RF in brucellosis patients with arthralgia was critical, nearly one-third of patients had RF positive. Elderly men brucellosis patients with arthralgia, wrist joint pain and elevated CRP were at high risk of positive RF. It is reminded that physicians should focus on differential diagnosis during clinical diagnosis and treatment, especially in brucellosis-endemic regions.
34572509 Adropin Serum Levels in Patients with Primary Sjögren's Syndrome. 2021 Aug 31 Primary Sjögren's syndrome (pSS) patients have higher prevalence of endothelial dysfunction and premature atherosclerosis. Recent studies investigated adropin, a secretory protein that can regulate lipid metabolism and insulin resistance and protect endothelial cells' function and that has an anti-inflammatory effect. The aim of this study was to determine adropin levels in pSS patients compared to healthy controls. Additional goals were exploring the correlation between adropin and several metabolic and immunological parameters in pSS, including disease specific antibodies, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), and Sjögren's Syndrome Disease Damage Index (SSDDI). This research included 52 pSS patients and 52 healthy controls. pSS patients have significantly higher adropin levels compared to the control group (3.76 ± 0.68 vs. 3.14 ± 0.69 ng/mL, p < 0.001). Correlation analysis showed that adropin levels in pSS patients have positive correlation with high-density lipoprotein (HDL) (r = 0.290, p = 0.036) and anti SSA/Ro52 antibodies (r = 0.307, p = 0.026) and negative correlation with SSDDI (r = -0.401, p = 0.003). Multivariant linear regression showed that adropin levels are independently associated with HDL (β ± SE, 0.903 ± 0.283, p = 0.002) and SSDDI (β ± SE, -0.202 ± 0.073, p = 0.008). Our findings imply that adropin could be involved in the pathophysiology of pSS, yet it remains to be elucidated in future studies whether adropin has a protective or detrimental role in this setting.
33493278 Characteristics and risk factors of relapses in patients with adult-onset Still's disease: 2021 Oct 2 OBJECTIVES: To describe the detailed characteristics and explore the potential risk factors of relapses in patients with adult-onset Still's disease (AOSD). METHODS: We enrolled patients with AOSD admitted to the Department of Rheumatology and Immunology, Ruijin Hospital from August 2016 to September 2019. Kaplan-Meier curves and the log rank test were used to estimate the cumulative relapse probability and persistent remission rate before the first occurrence of relapse. The multivariate Cox proportional hazard method was utilized to identify risk factors associated with relapses of AOSD. RESULTS: A total of 122 patients with AOSD were enrolled with a median follow-up of 12.6 months. Among them, 26 (21.3%) patients had at least one relapse. The cumulative relapse rates of AOSD patients were 14.42%, 21.79%, 24.81% and 28.57% at 6, 12, 18 and 36 months, respectively. According to the multivariate analysis, intensive treatment (odds ratio: 6.848; 95% CI: 2.441, 19.211) and macrophage activation syndrome (odds ratio: 4.020, 95% CI: 1.564, 10.322) were associated with increased risk of relapse. CONCLUSION: Our study indicated that relapses occurred in at least one-fifth of patients with AOSD, and patients with high disease severity at initial attack may have an increased risk of relapse, which needs more intensive therapy and close follow-up.