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ID PMID Title PublicationDate abstract
32911538 Untargeted lipidomics reveals specific lipid abnormalities in Sjögren's syndrome. 2021 Mar 2 OBJECTIVE: The relationship between serum lipid variations in SS and healthy controls was investigated to identify potential predictive lipid biomarkers. METHODS: Serum samples from 230 SS patients and 240 healthy controls were collected. The samples were analysed by ultrahigh-performance liquid chromatography coupled with Q Exactive™ spectrometry. Potential lipid biomarkers were screened through orthogonal projection to latent structures discriminant analysis and further evaluated by receiver operating characteristic analysis. RESULTS: A panel of three metabolites [phosphatidylcholine (18:0/22:5), triglyceride (16:0/18:0/18:1) and acylcarnitine (12:0)] was identified as a specific biomarker of SS. The receiver operating characteristic analysis showed that the panel had a sensitivity of 84.3% with a specificity of 74.8% in discriminating patients with SS from healthy controls. CONCLUSION: Our approach successfully identified serum biomarkers associated with SS patients. The potential lipid biomarkers indicated that SS metabolic disturbance might be associated with oxidized lipids, fatty acid oxidation and energy metabolism.
34723755 Uncovering potential single nucleotide polymorphisms, copy number variations and related s 2021 Dec Primary Sjogren's syndrome (pSS) is a complex systemic autoimmune disease, which is difficult to accurately diagnose due to symptom diversity in patients, especially at earlier stages. We tried to find potential single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and related signaling pathways. Genomic DNA was extracted from peripheral blood of 12 individuals (7 individuals from 3 pSS pedigrees and 5 sporadic cases) for whole-exome sequencing (WES) analysis. SNPs and CNVs were identified, followed by functional annotation of genes with SNPs and CNVs. Gene expression profile (involving 64 normal controls and 166 cases) was downloaded from the Gene Expression Omnibus database (GEO) dataset for differentially expression analysis. Sanger sequencing and in vitro validation was used to validate the identified SNPs and differentially expressed genes, respectively. A total of 5 SNPs were identified in both pedigrees and sporadic cases, such as FES, PPM1J, and TRAPPC9. A total of 3402 and 19 CNVs were identified in pedigrees and sporadic cases, respectively. Fifty-one differentially expressed genes were associated with immunity, such as BATF3, LAP3, BATF2, PARP9, and IL15RA. AMPK signaling pathway and cell adhesion molecules (CAMs) were the most significantly enriched signaling pathways of identified SNPs. Identified CNVs were associated with systemic lupus erythematosus, mineral absorption, and HTLV-I infection. IL2-STAT5 signaling, interferon-gamma response, and interferon-alpha response were significantly enriched immune related signaling pathways of identified differentially expressed genes. In conclusion, our study found some potential SNPs, CNVs, and related signaling pathways, which could be useful in understanding the pathological mechanism of pSS.
32840702 Design of an algorithm for the diagnostic approach of patients with joint pain. 2021 Apr BACKGROUND: Rheumatic diseases are a reason for frequent consultation with primary care doctors. Unfortunately, there is a high percentage of misdiagnosis. OBJECTIVE: To design an algorithm to be used by primary care physicians to improve the diagnostic approach of the patient with joint pain, and thus improve the diagnostic capacity in four rheumatic diseases. METHODS: Based on the information obtained from a literature review, we identified the main symptoms, signs, and paraclinical tests related to the diagnosis of rheumatoid arthritis, spondyloarthritis with peripheral involvement, systemic lupus erythematosus with joint involvement, and osteoarthritis. We conducted 3 consultations with a group of expert rheumatologists, using the Delphi technique, to design a diagnostic algorithm that has as a starting point "joint pain" as a common symptom for the four diseases. RESULTS: Thirty-nine rheumatologists from 18 countries of Ibero-America participated in the Delphi exercise. In the first consultation, we presented 94 items to the experts (35 symptoms, 31 signs, and 28 paraclinical tests) candidates to be part of the algorithm; 74 items (25 symptoms, 27 signs, and 22 paraclinical tests) were chosen. In the second consultation, the decision nodes of the algorithm were chosen, and in the third, its final structure was defined. The Delphi exercise lasted 8 months; 100% of the experts participated in the three consultations. CONCLUSION: We present an algorithm designed through an international consensus of experts, in which Delphi methodology was used, to support primary care physicians in the clinical approach to patients with joint pain. Key Points • We developed an algorithm with the participation of rheumatologists from 18 countries of Ibero-America, which gives a global vision of the clinical context of the patient with joint pain. • We integrated four rheumatic diseases into one tool with one common symptom: joint pain. It is a novel tool, as it is the first algorithm that will support the primary care physician in the consideration of four different rheumatic diseases. • It will improve the correct diagnosis and reduce the number of paraclinical tests requested by primary care physicians, in the management of patients with joint pain. This point was verified in a recently published study in the journal Rheumatology International (reference number 31).
34118343 Leojaponin inhibits NLRP3 inflammasome activation through restoration of autophagy via upr 2021 Oct 5 ETHNOPHARMACOLOGICAL RELEVANCE: Duan Teng Yimu decoction is a Chinese herbal medicine compound with proven therapeutic effects on inflammasome-related diseases, such as rheumatoid arthritis. This decoction consists of three Chinese herbal medicines, including Leonurus japonicus (L. japonicus), which promotes the blood circulation and exhibits detumescence activity, traditionally curing gynecologic and inflammasome diseases. AIM OF THE STUDY: To explore the anti-inflammasome activity and the underlying mechanisms of action of the compounds from L. japonicus. MATERIALS AND METHODS: A series of compounds were isolated from L. japonicus. Their anti-inflammasome activities were evaluated in macrophages that were co-stimulated by lipopolysaccharide (LPS) and NLRP3 inflammasome inducers. NLRP3 inflammasome formation and apoptosis speck like containing a CARD (ASC) oligomerization were evaluated by immunofluorescent microscopy and Western blot analysis. The regulation of autophagy after treatment of this compound was also evaluated. Lastly, in vivo activity of Leojaponin was analyzed in a mouse acute gouty arthritis model. RESULTS: Here we show that Leojaponin, a diterpenoid compound from L. japonicus, suppressed lactate dehydrogenase and IL-1β release in Nigericin-stimulated macrophages in a pyroptosis model. Leojaponin inhibits NLRP3 inflammasome activation in both J774A.1 cells and bone marrow-derived macrophages in a dose dependent manner. Moreover, Leojaponin suppressed NLRP3-mediated ASC specks formation and ASC oligomerization. These activities of Leojaponin depend on restoration of autophagy via promoting RAPTOR phosphorylation. Furthermore, Leojaponin ameliorated monosodium urate (MSU)-induced acute gouty arthritis in vivo. CONCLUSION: Our findings suggest that Leojaponin inhibits NLRP3 inflammasome activation through enhancing autophagy via RAPTOR phosphorylation, thereby highlighting Leojaponin as a potent drug for inflammasome-related diseases.
35062696 Reduced Humoral Response of SARS-CoV-2 Antibodies following Vaccination in Patients with I 2021 Dec 28 Background/Purpose: In light of the current COVID-19 pandemic, whether patients with rheumatic musculoskeletal disease (RMD) treated with conventional (cs) or biologic (b) disease-modifying drugs (DMARDs) exhibit an adequate immune response to the currently available SARS-CoV-2 vaccinations remains a major concern. There is an urgent need for more SARS-CoV-2 vaccine efficacy data to inform healthcare providers on the potential need for a booster vaccine. We established the 'Detection of SARS-CoV-2 antibodies in Danish Inflammatory Rheumatic Outpatients' study (DECODIR) in March 2021 in order to assess and compare the immunoglobulin G (IgG response) of the SARS-CoV-2 BNT162b2 vaccine (Pfizer, Groton, CT, USA/BioNTech, Mainz, Germany) and mRNA-1273 vaccine (Moderna, Cambridge, MA, USA) administered as part of the national vaccine roll out in patients with RMDs, irrespective of treatment. Patients' SARS-CoV-2 IgG level was used as proxy to determine vaccination response. Methods: The study is a longitudinal prospective cohort study in which the SARS-CoV-2 antibody response was measured and compared at baseline and at six weeks following vaccination. The study population consisted of patients with rheumatoid arthritis (RA), spondyloarthropathies (SpA), or psoriatic arthritis (PsA) receiving their outpatient treatment at the Danish Hospital for Rheumatic Diseases, Sonderborg. Bloods, patient reported outcome measurements (PROMS), clinical data, and treatment information (cs/bDMARD) were collected at baseline/6 weeks and documented in the Danish DANBIO registry. Commercially available antibody tests (ThermoFisher, Waltham, MA, USA) were used, and SARS-CoV-2 IgG levels were reported in EliA U/mL. Sufficient IgG response was defined as ≥10 EliA U/mL (manufacturers cut-off). Associations between antibody response, age, gender, disease (RA/PsA/SpA), no treatment or cs/bDMARD treatment, and disease activity were tested using proportional odds regression and bootstrapped tests of medians. Results were reported using mean, median (IqR), and bootstrapped 95% confidence interval (CI) of the median. Results: A total of 243 patients were included. We observed a significant increase in IgG levels (median of <0.7 EliA U/mL at baseline versus 34.5 EliA U/mL at 6 weeks). Seventy-two patients (32%) had an insufficient IgG response. The median IgG level in patients treated with cs/bDMARD combination therapy was significantly lower compared to patients without any DMARD treatment (12 EliA U/mL vs. 92 EilA U/mL (p < 0.01)). Conclusion: Patients treated with a combination of cs/bDMARD are at significantly higher risk of an inadequate response to SARS-CoV-2 vaccines as measured by IgG level compared to patients without DMARD treatment. IgG SARS-CoV-2 are only part of the immune response, and further data are urgently needed. At present, our results may inform healthcare providers and policy makers on the decision for the need of a booster vaccine in this particular patient group.
33844457 ICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immu 2021 Oct OBJECTIVE: Macrophage migration inhibitory factor (MIF) is an inflammatory and neurorendocrine mediator that counterregulates glucocorticoid immunosuppression. MIF polymorphisms, which comprise a variant promoter microsatellite (-794 CATT(5-8) ), are linked genetically to autoimmune disease severity and to glucocorticoid resistance. While invasive stimuli increase MIF expression, MIF also is up-regulated by glucocorticoids, which serve as a physiologic regulator of inflammatory responses. This study was undertaken to define interactions between the MIF promoter, the glucocorticoid receptor (GR), and the transcription factor inverted CCAAT box binding protein 90 kd (ICBP90) (also referred to as UHRF1), which binds to the promoter in a -794 CATT(5-8) length-dependent manner, to regulate MIF transcription. METHODS: Interactions of ICBP90, GR, and activator protein 1 (AP-1) with MIF -794 CATT(5-8) promoter constructs were assessed by coimmunoprecipitation, Western blotting, and genetic knockdown. Nuclear colocalization studies were performed using anti-transcription factor antibodies and confocal microscopy of glucocorticoid-treated cells. MIF transcription was studied in CEM-C7 T cells, and the impact of the MIF -794 CATT(5-8) microsatellite variation confirmed in peripheral blood T cells and in rheumatoid synovial fibroblasts of defined MIF genotype. Functional interactions were quantified by apoptosis and apoptotic signaling in high- and low-genotypic MIF-expressing human cells. RESULTS: We defined functional interactions between the transcription factors ICBP90, the GR, and AP-1 that up-regulated MIF transcription in a -794 CATT(5-8) length-dependent manner. Experimental reduction of ICBP90, GR, or AP-1 decreased MIF expression and increased glucocorticoid sensitivity, leading to enhanced apoptosis in T lymphocytes and in rheumatoid synovial fibroblasts. CONCLUSION: These findings suggest a mechanism for genetic variation of glucocorticoid-regulated MIF transcription, with implications for autoimmune disease severity and glucocorticoid responsiveness.
33480606 Influence of Comorbidities on Short-Term Functional Outcomes After Unilateral Total Knee A 2021 Nov 1 OBJECTIVE: The aim of the study was to determine the effect of comorbidities on physical function and quality of life of patients at 3 mos after total knee arthroplasty. DESIGN: Data from 140 patients who underwent a primary unilateral total knee arthroplasty were examined retrospectively. Comorbidities were osteoporosis, presarcopenia, degenerative spine disease, diabetes, and hypertension. All patients completed the following: range of motion, stair climbing test, 6-min walk test, Timed Up and Go Test, peak torque of the knee extensor and flexor, instrumental gait analysis, Western Ontario McMaster Universities Osteoarthritis Index, and EuroQoL five-dimension questionnaire. RESULTS: Univariate analyses revealed that osteoporosis led to a significantly longer time to complete the stair climbing test-ascent, stair climbing test-descent, and Timed Up and Go Test and to lower scores for the 6-min walk test and peak torque of the knee extensor. Patients with degenerative spine disease showed significant negative scores for knee extension range of motion. Diabetes showed a negative correlation with peak torque of the knee extensor and knee flexion range of motion, as well as a higher Western Ontario McMaster Universities Osteoarthritis Index-stiffness score. Multivariable linear regression analysis showed that Western Ontario McMaster Universities Osteoarthritis Index-stiffness remained independently associated with diabetes. Six-minute walk test, Timed Up and Go Test, stair climbing test-ascent, and peak torque of the knee extensors showed a significant association with osteoporosis. CONCLUSIONS: Comorbidities, particularly osteoporosis and diabetes, affect short-term functional outcomes 3 mos after total knee arthroplasty.
34009464 Antegrade intramedullary nailing in comminuted, open metacarpal bone fracture: maintenance 2021 Oct PURPOSE: The purpose of this study was to evaluate the radiological and clinical outcomes of treatment of comminuted open fractures of the metacarpal bone (MCB) with associated injuries to soft tissues, tendons, and neurovascular structures using antegrade intramedullary nailing (AIN) at least 2 years postoperatively. METHODS: Between January 2008 and December 2017, a total of 27 patients who met the inclusion/exclusion criteria were included in this study. The inclusion criterion was open and comminuted fracture (with/without segmental bone defects). We evaluated simple radiograph and computed tomography (CT) findings and clinical conditions (visual analog scale [VAS] pain score and Disabilities of the Arm, Shoulder, and Hand [DASH] score), including active range of motion (ROM) at metacarpophalangeal joint (MP) and grip strength at final follow-up. RESULTS: The mean preoperative angulation was 29.63° ± 7.59° and the mean shortening was 9.30 ± 2.38 mm. Union was achieved at mean 12.3 weeks postoperatively, without any complications due to operative treatment. The dorsal angulation measured on the CT scans, shortening on simple radiographs was significantly improved (10.26 °± 3.19°, 0.52 ± 1.05 mm, respectively). The final VAS and DASH scores were 0.41 ± 0.64 and 3.6 ± 2.47, respectively, indicating satisfactory outcomes. The final ROM was 85.0° ± 3.67°. The mean final grip strength was 89.56 ± 5.69% relative to the normal side. A mean extension lag at the MP joint of 12° was noted in three patients; however, it was resolved by additional tenolysis. CONCLUSIONS: AIN is a simple method for fixation of open comminuted metacarpal fractures accompanied by soft tissue injury. The simplicity of the method is beneficial for repairing associated injured structures and healing soft tissue. Minimized additional damage around the MCB during surgery and good stability resulted in satisfactory bony union with minimal angulation, shortening, and rotation. LEVEL OF EVIDENCE: Level IV, Retrospective case series.
33832704 Corrective osteotomy for malunion of distal diaphyseal/metaphyseal radius or ulna fracture 2021 Aug BACKGROUND: We postulated that residual distal radioulnar joint (DRUJ) instability after distal diaphyseal or metaphyseal fracture in the radius or ulna may occur due to malaligned or malunited bony structures as well as primary or secondary soft issue stabiliser. Here, we report the outcomes of corrective osteotomy in a retrospective study. METHODS: Patients undergoing the osteotomy for DRUJ instability between March 2000 and February 2018 were included in the study. Thirteen patients were evaluated. The initial injury occurred at a mean age of 12.3 years and corrective osteotomy was performed at a mean age of 20.8 years. The mean follow-up period was 33.1 months. The male to female ratio was 8:5 and the corrected radius/ulna ratio was 11:2. DRUJ instability was diagnosed clinically and radiologically based on the stress/clunk test and the distance between the cortex of the radius, and the radioulnar ratio. All osteotomies in the radius and ulna were of the open wedge type and were performed using plates/screws. RESULTS: The radioulnar ratio was significantly higher than the normal ratio (p < 0.001). All osteotomies healed well without any serious complications. The preoperative distance between the cortex of the radius and ulna was significantly decreased at the final follow-up, from 4.74 ± 0.82 to 1.16 ± 0.46 mm (p < 0.001). Positive findings of two instability tests were all converted to negative. The ranges of motion of the flexion-extension and pronation-supination arcs were significantly improved. Finally, preoperative VAS pain and DASH scores improved to 0.23 ± 0.44 and 3.92 ± 1.84, respectively (p < 0.001). CONCLUSIONS: Malunited radius or ulna plays a role in DRUJ instability, affecting the bony geometry in terms of the relationship between the sigmoid notch and ulnar head. Treatment of malunion by corrective osteotomy represents a useful option for resolving instability. LEVEL OF EVIDENCE: Level IV, Retrospective therapeutic study.
32797295 Revision osteosynthesis after primary treatment of atypical ulnar fractures associated wit 2021 Nov BACKGROUND: We performed revision surgeries to treat nonunion of bisphosphonate-associated ulnar fractures that had originally been treated, after misdiagnosis, using the typical open reduction/internal fixation (ORIF). METHODS: Of nine cases of ulnar nonunion initially treated at other institutions, we performed revision surgeries on four that met our inclusion/exclusion criteria. All previous implants were removed; the areas of nonunion were resected, and strut bone grafts were inserted and fixed with locking plates. Radiological assessments were performed monthly for 3 months after surgery and then every 3 months for 1 year. RESULTS: All patients were female, with a mean age of 71.8 years. All patients had been taking bisphosphonate for a mean of 7.2 years. The primary fixation methods used at other institutions were intra-medullary nailing (n = 1) and placement of 3.5-mm locking plates (n = 3). In one patient (patient 1), the contralateral (right) ulna developed a new fracture at 1 month after revision surgery on the left ulna. Another patient (patient 3) exhibited an incomplete fracture in the contralateral (right) ulna. All four patients exhibited hip fractures (bilateral in three). All revisions resulted in final union at a mean of 4.8 months postoperatively. CONCLUSION: Atypical ulnar fractures should be suspected in elderly women on long-term bisphosphonate treatment. Union will fail with standard ORIF for atypical ulnar fractures, because the fracture occurred due to compromised normal bone metabolism as reflected in the bone resorption, remodeling, and healing processes. Revision osteosynthesis using a locking plate with callus resection and strut/cancellous bone graft provided satisfactory results. LEVEL OF EVIDENCE: Therapeutic level IV.
33856543 Clinical characteristics and outcome of COVID-19 in patients with rheumatic diseases. 2021 Jun This study aimed to assess the baseline characteristics and clinical outcomes of coronavirus disease 2019 (COVID-19) in patients with rheumatic diseases and identify the risk factors associated with severe COVID-19 pneumonia. This was a retrospective study in a tertiary care center conducted through the period between March 2020 and November 2020 and included all adult patients with rheumatic diseases who tested positive on the COVID-19 polymerase chain reaction (PCR) test. We assessed the patients' demographic data, history of rheumatic disease, COVID-19 symptoms and experimental treatment, if any, their disease course, and outcome. In all, 47 patients were included, and most were females. The commonest rheumatic diseases were rheumatoid arthritis (53.2%), followed by systemic lupus erythematosus (21.3%), and psoriatic arthritis (10.6%). Methotrexate and hydroxychloroquine were the most commonly used disease-modifying anti-rheumatic drugs in 36.1% and 25.5%, respectively. Out of 47 patients, 48.9% required hospitalization with a median hospital stay of 7 days. Severe COVID-19 pneumonia, defined as clinical signs of pneumonia plus one of the following: respiratory rate > 30 bpm, severe respiratory distress, or oxygen saturation < 90% in room air was observed in 19.1% of the patients, and one patient died. We found that elderly patients with a mean age of 65.3 years were more likely to develop severe COVID-19 pneumonia and that was statistically significant. Our study showed that elderly patients with a mean age of 65 years and having rheumatic diseases had an increased risk of hospital admission and development of severe COVID-19 pneumonia.
33085850 Modifications in Systemic Rheumatic Disease Medications: Patients' Perspectives During the 2021 Jun OBJECTIVE: Concerns about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have led to changes or discontinuation of immunosuppressive medications among patients with systemic rheumatic disease. Our goal was to assess patients' perspectives regarding medication modifications and deviations from planned uses during the height of the pandemic. METHODS: Adult patients of 13 rheumatologists at an academic center with physician-diagnosed rheumatic disease and prescribed disease-modifying medications were interviewed by telephone and asked open-ended questions about the impact of SARS-CoV-2 on their medications. Responses were analyzed using content and thematic analyses to generate categories that described patterns of medication modification. RESULTS: A total of 112 patients (mean age 50 years, 86% women, 34% non-White race or Latino ethnicity) with diverse diagnoses (30% lupus, 26% rheumatoid arthritis, 44% other) who were taking various medications were enrolled. Patients reported clinically relevant issues that were iteratively reviewed to generate unique categories of medication modification: medications and increased or decreased risk of SARS-CoV-2 infection; role of hydroxychloroquine; maintaining medication status quo; role of glucocorticoids; increasing or decreasing existing medications in relation to clinical disease activity; postponing infusions; and medication plan if infected by SARS-CoV-2. Some modifications were suboptimal for disease control but were made to mitigate infection risk and to minimize potential harm when patients were unable to obtain laboratory tests and physical examinations due to cessation of in-person office visits. CONCLUSION: During the height of the pandemic, substantial medication modifications were made that, in some cases, were temporizing measures and deviations from planned regimens. Future studies will assess short- and long-term sequelae of these medication modifications.
34741435 TNFi Cycling Versus Changing Mechanism of Action in TNFi-Experienced Patients: Result of t 2022 Jan OBJECTIVE: Comparative effectiveness research can inform treatment decisions regarding the choice of biologics for rheumatoid arthritis (RA). The objective of this study is to compare the efficacy of tumor necrosis factor inhibitors (TNFis) and non-TNFis (nTNFis) in real-world patients with RA and past TNFi experience. METHODS: Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) was nested within the United States Corrona registry. Adult patients with RA with moderate to high disease activity (Clinical Disease Activity Index [CDAI] >10) with exposure to one or more prior TNFis who were switching to a new TNFi or nTNFi (choice of therapy per physician choice) were enrolled. The primary outcome was the achievement of low disease activity (LDA) at 12 months (CDAI ≤10; disease activity score in 28 joints based on C-reactive protein [DAS28-CRP] <2.67). Propensity score modeling probability of treatment with nTNFi versus TNFi adjusted for imbalanced factors. The response rate was modeled using mixed-effect logistic regression models, adjusting for a priori and imbalanced baseline factors and accounting for the practice-related treatment patterns. RESULTS: After applying inclusion criteria, 939 biologic initiations were analyzed, 505 (53.7%) nTNFis and 434 (46.3%) TNFis. Patients who started nTNFis were significantly more likely to have longer disease duration, more prior TNFi use, and higher patient fatigue scores and were more likely to have government insurance. At 12 months, 28% of nTNFi and 24% of TNFi initiators were in LDA by CDAI, and 22% of nTNFi and 19% of TNFi initiators were in LDA by DAS28-CRP. After multivariable adjustment and controlling for the influence of site-related confounding, there were no significant differences in the likelihood to reach LDA by CDAI (adjusted odds ratio [aOR] = 1.12; 95% confidence interval [CI], 0.78-1.62) or DAS28-CRP (aOR = 1.16; 95% CI, 0.77-1.75). CONCLUSION: In this large, real-world study enrolling patients with RA with prior TNFi exposure, switching to an nTNFi biologic was comparable in its clinical effectiveness with switching to another TNFi.
33997149 The progress of medication-related osteonecrosis of the jaw with conservative initial trea 2021 Jun This retrospective study aimed to examine the course and prognosis of medication-related osteonecrosis of the jaw (MRONJ) initially treated conservatively and the effects of various factors affecting treatment outcomes. We evaluated 129 patients with MRONJ between January 2008 and December 2018 at a university hospital. The factors examined included sex, age, stage of MRONJ (1-3), type of bone modifying agents (bisphosphonate or denosumab), primary disease (osteoporosis or malignant tumor), medical history (diabetes and rheumatoid arthritis), use of corticosteroids, the trigger of MRONJ (teeth extraction or others), and separation of sequestrum, using logistic regression analysis. Patients with MRONJ were treated conservatively as the initial treatment in accordance with the position paper of the American Association of Oral and Maxillofacial Surgeons. Of the 129 patients, 59 (45.7%) were cured, and the condition of 70 (54.3%) remained unchanged or worsened. The overall cure rates at 12, 36, and 60 months were 25.8%, 50.8%, and 72.4% respectively. The cure rate of stage 1 was lower than that of stages 2 and 3 at 80 months. In multivariate analysis, it was found that 37 (64.9%) of 57 patients with osteoporosis as a primary disease were cured (odds ratio [OR], 7.7; 95% confidence interval [CI], 2.4-24.4). In addition, 40 (69.0%) of 58 patients with separation of sequestrum were cured (OR, 8.9; 95% CI, 3.4-23.5). The cure rate was significantly higher in patients with osteoporosis than in those with cancer when the treatment outcomes of primary disease were compared using the Kaplan-Meier method (p < 0.01). It was also significantly higher in patients who had separation of sequestrum than in those who did not (p < 0.05). Our results suggest that primary disease and separation of sequestrum were associated with favorable outcomes in patients with MRONJ initially treated conservatively. MRONJ had a poor prognosis with conventional treatment carried according to the stage of the disease. This was especially prominent when conservative treatment was employed for mild cases.
33582917 Triptolide Inhibits Expression of Inflammatory Cytokines and Proliferation of Fibroblast-l 2021 Feb Triptolide, a component of the Chinese herb Tripterygium wilfordii Hook F, has been proved to be effective in the treatment of rheumatoid arthritis (RA). However, its underlying mechanisms on RA have not yet been well established. We observed the inhibitory effect of triptolide on the expression of inflammatory cytokines and proliferation of fibroblast-like synoviocytes (FLS) induced by the complex of interleukin-6 (IL-6) and the soluble form of the IL-6 receptor (sIL-6R). Furthermore, to clarify the underlying mechanisms, we treated FLS with the Janus-activated kinase 2 (JAK2) inhibitor/signal transducer and activator of transcription 3 (STAT3) activation blocker AZD1480. In this study, immunohistochemical staining was used to identify vimentin (+) and CD68 (-) in FLS. The FLS proliferation was measured by cell proliferation assay, and the cell cycles were analyzed by flow cytometry. Furthermore, ELISA was used to detect the expression of the inflammatory factors in culture solution. The expression levels of p-JAK2, JAK2, p-STAT3 and STAT3 were investigated through Western blotting analysis. The results showed that IL-6/sIL-6R significantly increased the cell proliferation and expression of inflammatory cytokines, including IL-6, interleukin-1β (IL-1β) and vascular endothelial growth factor (VEGF). Triptolide or AZD1480 inhibited the cell proliferation and inflammatory cytokine expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3. The study suggested that the physiological effects of triptolide on RA were due to its contribution to the inhibition of the inflammatory cytokine expression and FLS proliferation by suppressing the JAK2/STAT3 signaling pathway. It may provide an innovative insight into the effect of triptolide in preventing RA pathogenesis.
33471137 Preexisting autoimmune disease and immune-related adverse events associated with anti-PD-1 2021 Aug BACKGROUND: Limited data are available on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with preexisting autoimmune diseases (PAD). METHODS: Retrospective study of patients with PAD referred for rheumatologic evaluation prior to starting or during immunotherapy between January 2013 and July 2019 from 10 academic sites across Canada. Data were extracted by chart review using a standardized form. RESULTS: Twenty-seven patients with PAD on ICI therapy were identified. The most common PADs were rheumatoid arthritis (30%), psoriasis/psoriatic arthritis (30%), inflammatory bowel disease (IBD, 15%) and axial spondyloarthritis (11%), and the most frequently observed cancers were lung cancer and melanoma. All patients received anti-PD-1 therapies, and 2 received additional sequential anti-CTLA-4 therapy. PAD exacerbations occurred in 52% over a median (IQR) follow-up of 11.0 (6.0-17.5) months, with 14% being severe, 57% requiring corticosteroids, 50% requiring immunosuppression and 14% requiring ICI discontinuation. Flares were generally more frequent and severe in patients who previously required more intensive immunosuppression (i.e., biologics). Flares occurred despite background immunosuppression at the time of ICI initiation. In patients with preexisting psoriasis, IBD and axial spondyloarthritis, rheumatic immune-related adverse events (irAEs), mostly polyarthritis and tenosynovitis, were frequently observed. Tumor progression was not associated with exposure to immunosuppressive drugs before or after ICI initiation and was numerically less frequent in patients with irAEs. CONCLUSION: PAD exacerbations in the context of ICI treatment are common, although generally mild, and occur despite background immunosuppression. Exacerbations are more frequent and severe in patients on more intensive immunosuppressive therapies pre-immunotherapy.
32300866 Patients' beliefs and behaviours are associated with perceptions of safety and concerns in 2021 Jan Although patient acceptance is important for biosimilar adoption and reducing healthcare costs, many patients perceive biosimilars to be unsafe and have concerns about switching. Studies show that patients' characteristics influence negative perceptions toward generic drugs, but little research has explored biosimilar acceptance. This study examines which demographic and psychological characteristics are associated with patients' safety perceptions and concerns about switching to biosimilars. Ninety-six patients taking bio-originators for rheumatic conditions (65% for rheumatoid arthritis) completed the Brief Illness Perceptions Questionnaire, Beliefs about Medicines Questionnaire and Perceived Sensitivity to Medicines Scale. Demographic factors, information seeking, concerns about switching and safety perceptions were also assessed. Pearson's correlations and hierarchical linear regressions were conducted to explore whether patient characteristics are associated with perceptions of biosimilars. Negative safety perceptions were associated with being female, short-term bio-originator use, illness beliefs, seeking health information online, high perceived sensitivity to medicines and negative beliefs about medicines. Only being female (β = 0.24, P = 0.02) was independently associated. More concerns about switching were associated with being female, illness beliefs, high perceived sensitivity to medicines, information-seeking behaviours and preferring innovator drugs. Seeking health information online (β = 0.20, P = 0.04), preferring innovator drugs (β = 0.29, P = 0.004) and stronger emotional responses (β = 0.26, P = 0.01) were independently associated. Perceived bio-originator effectiveness was inversely associated with preferring biosimilars (r(s)=  - 0.33, P < 0.001). Patients who have stronger emotional responses to their condition, are females, seek health information online and prefer innovator drugs that have more negative perceptions about biosimilars. Experiences with bio-originators influence attitudes towards switching.
34296811 Maternal exposure to hydroxychloroquine and birth defects. 2021 Oct 15 BACKGROUND: Hydroxychloroquine is a treatment for rheumatic disease and considered safe during pregnancy. Interest in hydroxychloroquine has increased as it is being examined as a potential treatment and prophylaxis for coronavirus disease 2019. Data on the risks of specific birth defects associated with hydroxychloroquine use are sparse. METHODS: Using data from two case-control studies (National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study), we described women who reported hydroxychloroquine use in pregnancy and the presence of specific major birth defects in their offspring. Cases had at least one major birth defect and controls were live-born healthy infants. Women self-reported medication use information in the few months before pregnancy through delivery. RESULTS: In total, 0.06% (19/31,468) of case and 0.04% (5/11,614) of control mothers in National Birth Defects Prevention Study, and 0.04% (11/29,838) of case and 0.05% (7/12,868) of control mothers in Birth Defects Study reported hydroxychloroquine use. Hydroxychloroquine users had complicated medical histories and frequent medication use for a variety of conditions. The observed birth defects among women taking hydroxychloroquine were varied and included nine oral cleft cases; the elevated observed:expected ratios for specific oral cleft phenotypes and for oral clefts overall had 95% confidence intervals that included 1.0. CONCLUSION: While teratogens typically produce a specific pattern of birth defects, the observed birth defects among the hydroxychloroquine-exposed women did not present a clear pattern, suggesting no meaningful evidence for the risk of specific birth defects. The number of exposed cases is small; results should be interpreted cautiously.
34655959 Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilat 2021 Nov INTRODUCTION: Ventilator-induced diaphragm dysfunction (VIDD) is an important phenomenon that has been repeatedly demonstrated in experimental and clinical models of mechanical ventilation. Even a few hours of MV initiates signaling cascades that result in, first, reduced specific force, and later, atrophy of diaphragm muscle fibers. This severe, progressive weakness of the critical ventilatory muscle results in increased duration of MV and thus increased MV-associated complications/deaths. A drug that could prevent VIDD would likely have a major positive impact on intensive care unit outcomes. We identified the JAK/STAT pathway as important in VIDD and then demonstrated that JAK inhibition prevents VIDD in rats. We subsequently developed a clinical model of VIDD demonstrating reduced contractile force of isolated diaphragm fibers harvested after ∼7 vs ∼1 h of MV during a thoracic surgical procedure. MATERIALS AND METHODS: The NIH-funded clinical trial that has been initiated is a prospective, placebo controlled trial: subjects undergoing esophagectomy are randomized to receive 6 preoperative doses of the FDA-approved JAK inhibitor Tofacitinib (commonly used for rheumatoid arthritis) vs. placebo. The primary outcome variable will be the difference in the reduction that occurs in force generation of diaphragm single muscle fibers (normalized to their cross-sectional area), in the Tofacitinib vs. placebo subjects, over 6 h of MV. DISCUSSION: This trial represents a first-in-human, mechanistic clinical trial of a drug to prevent VIDD. It will provide proof-of-concept in human subjects whether JAK inhibition prevents clinical VIDD, and if successful, will support an ICU-based clinical trial that would determine whether JAK inhibition impacts clinical outcome variables such as duration of MV and mortality.
33892719 Homozygous variant p. Arg90His in NCF1 is associated with early-onset Interferonopathy: a 2021 Apr 23 BACKGROUND: Biallelic loss-of-function variants in NCF1 lead to reactive oxygen species deficiency and chronic granulomatous disease (CGD). Heterozygosity for the p.Arg90His variant in NCF1 has been associated with susceptibility to systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome in adult patients. This study demonstrates the association of the homozygous p.Arg90His variant with interferonopathy with features of autoinflammation and autoimmunity in a pediatric patient. CASE PRESENTATION: A 5-year old female of Indian ancestry with early-onset recurrent fever and headache, and persistently elevated antinuclear, anti-Ro, and anti-La antibodies was found to carry the homozygous p.Arg90His variant in NCF1 through exome sequencing. Her unaffected parents and three other siblings were carriers for the mutant allele. Because the presence of two NCF1 pseudogenes, this variant was confirmed by independent genotyping methods. Her intracellular neutrophil oxidative burst and NCF1 expression levels were normal, and no clinical features of CGD were apparent. Gene expression analysis in peripheral blood detected an interferon gene expression signature, which was further supported by cytokine analyses of supernatants of cultured patient's cells. These findings suggested that her inflammatory disease is at least in part mediated by type I interferons. While her fever episodes responded well to systemic steroids, treatment with the JAK inhibitor tofacitinib resulted in decreased serum ferritin levels and reduced frequency of fevers. CONCLUSION: Homozygosity for p.Arg90His in NCF1 should be considered contributory in young patients with an atypical systemic inflammatory antecedent phenotype that may evolve into autoimmunity later in life. The complex genomic organization of NCF1 poses a difficulty for high-throughput genotyping techniques and variants in this gene should be carefully evaluated when using the next generation and Sanger sequencing technologies. The p.Arg90His variant is found at a variable allele frequency in different populations, and is higher in people of South East Asian ancestry. In complex genetic diseases such as SLE, other rare and common susceptibility alleles might be necessary for the full disease expressivity.