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ID PMID Title PublicationDate abstract
34916687 [Clinical and immunological characteristics of 88 cases of overlap myositis]. 2021 Dec 18 OBJECTIVE: To investigate the clinical and immunological characteristics of overlap myositis (OM) patients. METHODS: The data of 368 patients with idiopathic inflammatory myopathies (IIMs) admitted to Peking University People's Hospital from January 2004 to August 2020 were analyzed retrospectively, including demographic characteristics, clinical characteristics (including fever, Gottron' s sign/papules, Heliotrope rash, V-sign, Shawl sign, Mechanic' s hands, skin ulceration, periungual erythema, subcutaneous calcinosis, dysphagia, myalgia, myasthenia, arthritis, Raynaud' s phenomenon, interstitial lung disease, pulmonary hypertension and myocardial involvement), laboratory characteristics, immunological characteristics [including antinuclear antibodies, rheumatoid factors, myositis-associated autoantibodies (MAAs) and myositis-specific autoantibodies (MSAs)] and survival. The clinical and immunological characteristics and prognostic differences of OM and non-OM were compared. The Kaplan-Meier and Log Rank methods were used to analyze the survival. RESULTS: A total of 368 patients were included. 23.9% (88/368) of IIMs patients were OM patients. Among the 88 OM patients, 85.2% (75/88) of them were female, and the median interval between disease onset and diagnosis was 13.5 months. The incidence of overlapped connective tissue diseases in the OM patients was dermatomyositis (DM) in 60.2%, polymyositis (PM) in 3.4%, immune-mediated necrotizing myopathy (IMNM) in 2.3% and anti-synthetase syndrome (ASS) in 34.1%. Compared with the non-OM patients, the proportion of the females in the OM patients was higher (85.2% vs. 72.1%, P=0.016), the OM patients had longer disease duration [13.5(4.5, 48.0) months vs. 4.0(2.0, 12.0) months, P < 0.001]. As for clinical characteristics, compared with the non-OM patients, the incidence of V-sign (25.0% vs. 44.6%, P=0.001) and periungual erythema (8.0% vs. 19.6%, P=0.013) were lower; the incidence of Raynaud's phenomenon (14.8% vs. 1.8%, P < 0.001), interstitial pneumonia (88.6% vs. 72.1%, P=0.001), pulmonary hypertension (22.7% vs. 7.5%, P < 0.001) and myocardial involvement (18.2% vs. 9.3%, P=0.033) were higher. As for immunological characteristics, compared with the non-OM patients, the incidence of elevated aspartate aminotransferase (AST) (31.8% vs. 45.0%, P=0.035) was lower and elevated C-reactive protein (CRP) (58.0% vs. 44.6%, P=0.037) was higher; the positive rates of antinuclear antibodies (ANA) (85.1% vs. 63.4%, P=0.001) and rheumatoid factors (RF) (40.2% vs. 17.8%, P < 0.001) and anti-Ro-52 (71.6% vs. 56.1%, P=0.038) in serum were higher. There was no significant difference in the survival between the OM patients and non-OM patients. CONCLUSION: Pulmonary hypertension and myocardial involvement were frequently observed in OM.
34174253 McH-lpr/lpr-RA1 mice: A novel spontaneous mouse model of autoimmune sialadenitis. 2021 Sep Many studies of the autoimmune disease Sjögren's syndrome have been performed using spontaneous mouse models. In the present study, we describe the characteristics of McH/lpr-RA1 mice and propose their use as a novel murine model of autoimmune sialadenitis. The McH/lpr-RA1 mouse is a recombinant congenic strain derived from generation F54 or more of MRL-Fas(lpr) x (MRL- Fas(lpr) x C3H- Fas(lpr)) F1. We show for the first time that this mouse spontaneously develops autoimmune sialadenitis and vasculitis in submandibular gland tissues. Sialadenitis was accompanied by extensive inflammatory cell infiltration and tissue destruction. Immunohistochemical studies revealed that the salivary gland lesions strongly expressed four sialadenitis-related molecules: SSA and SSB (autoantigens of Sjögren's syndrome), gp91phox (an accelerator of reactive oxygen species production) and single strand DNA (a marker of apoptotic cells). In contrast, expression of aquaporin-5 (AQP5), which stimulates salivary secretion was weak or negligible. Statistical correlation analyses indicated that the apoptosis of salivary gland cells provoked by oxidative stress contributed to the severe sialadenitis and reduced expression of AQP5. Our study has demonstrated that McH/lpr-RA1 mice spontaneously develop the pathognomonic features of autoimmune sialadenitis and thus could be used as a new animal model of Sjögren's syndrome.
34932077 Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Th 2021 Dec 21 IMPORTANCE: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. OBJECTIVE: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. DESIGN, SETTING, AND PARTICIPANTS: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. INTERVENTIONS: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). MAIN OUTCOME AND MEASURES: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. RESULTS: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. CONCLUSIONS AND RELEVANCE: Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03074656.
34373464 Metagenomic analysis revealed the potential role of gut microbiome in gout. 2021 Aug 9 Emerging evidence indicates an association between gut microbiome and arthritis diseases including gout. However, how and which gut bacteria affect host urate degradation and inflammation in gout remains unclear. Here we performed a metagenome analysis on 307 fecal samples from 102 gout patients and 86 healthy controls. Gout metagenomes significantly differed from those of healthy controls. The relative abundances of Prevotella, Fusobacterium, and Bacteroides were increased in gout, whereas those of Enterobacteriaceae and butyrate-producing species were decreased. Functionally, gout patients had greater abundances for genes in fructose, mannose metabolism and lipid A biosynthesis, and lower for genes in urate degradation and short chain fatty acid production. A three-pronged association between metagenomic species, functions and clinical parameters revealed that decreased abundances of species in Enterobacteriaceae were associated with reduced amino acid metabolism and environmental sensing, which together contribute to increased serum uric acid and C-reactive protein levels in gout. A random forest classifier based on three gut microbial genes showed high predictivity for gout in both discovery and validation cohorts (0.91 and 0.80 accuracy), with high specificity in the context of other chronic disorders. Longitudinal analysis showed that uric-acid-lowering and anti-inflammatory drugs partially restored gut microbiota after 24-week treatment. Comparative analysis with obesity, type 2 diabetes, ankylosing spondylitis and rheumatoid arthritis indicated that gout metagenomes were more similar to those of autoimmune than metabolic diseases. Our results suggest that gut dysbiosis was associated with dysregulated host urate degradation and systemic inflammation and may be used as non-invasive diagnostic markers for gout.
35003062 The Tyrosine Kinase Tec Regulates Effector Th17 Differentiation, Pathogenicity, and Plasti 2021 T helper (Th) 17 cells are not only key in controlling infections mediated by extracellular bacteria and fungi but are also triggering autoimmune responses. Th17 cells comprise heterogeneous subsets, some with pathogenic functions. They can cease to secrete their hallmark cytokine IL-17A and even convert to other T helper lineages, a process known as transdifferentiation relying on plasticity. Both pathogenicity and plasticity are tightly linked to IL-23 signaling. Here, we show that the protein tyrosine kinase Tec is highly induced in Th17 cells. Th17 differentiation was enhanced at low interleukin-6 (IL-6) concentrations in absence of Tec, which correlates with increased STAT3 phosphorylation and higher Il23r expression. Therefore, we uncovered a function for Tec in the IL-6 sensing via STAT3 by CD4(+) T cells, defining Tec as a fine-tuning negative regulator of Th17 differentiation. Subsequently, by using the IL-17A fate mapping mouse combined with in vivo adoptive transfer models, we demonstrated that Tec not only restrained effector Th17 differentiation but also pathogenicity and plasticity in a T-cell intrinsic manner. Our data further suggest that Tec regulates inflammatory Th17-driven immune responses directly impacting disease severity in a T-cell-driven colitis model. Notably, consistent with the in vitro findings, elevated levels of the IL-23 receptor (IL-23R) were observed on intestinal pre- and postconversion Th17 cells isolated from diseased Tec(-/-) mice subjected to adoptive transfer colitis, highlighting a fundamental role of Tec in restraining IL-23R expression, likely via the IL-6-STAT3 signaling axis. Taken together, these findings identify Tec as a negative regulator of Th17 differentiation, pathogenicity, and plasticity, contributing to the mechanisms which help T cells to orchestrate optimal immune protection and to restrain immunopathology.
34959826 Effect of Crocus sativus (Saffron) Intake on Top of Standard Treatment, on Disease Outcome 2021 Nov 27 Rheumatic diseases (RDs) are often complicated by chronic symptoms and frequent side-effects associated with their treatment. Saffron, a spice derived from the Crocus sativus L. flower, is a popular complementary and alternative medicine among patients with RDs. The present systematic review aimed to summarize the available evidence regarding the efficacy of supplementation with saffron on disease outcomes and comorbidities in patients with RD diagnoses. PubMed, CENTRAL, clinicaltrials.gov and the grey literature were searched until October 2021, and relevant randomized controlled trials (RCTs) were screened for eligibility using Rayyan. Risk of bias was assessed using the Cochrane's Risk of Bias-2.0 (RoB) tool. A synthesis without meta-analysis (SWiM) was performed by vote counting and an effect direction plot was created. Out of 125 reports, seven fulfilled the eligibility criteria belonging to five RCTs and were included in the SWiM. The RCTs involved patients with rheumatoid arthritis, osteoarthritis and fibromyalgia, and evaluated outcomes related to pain, disease activity, depression, immune response, inflammation, oxidative stress, health, fatigue and functional ability. The majority of trials demonstrated some concerns regarding overall bias. Moreover, the majority of trialists failed to adhere to the formula elaborations suggested by the CONSORT statement for RCTs incorporating herbal medicine interventions. Standardization of herbal medicine confirms its identity, purity and quality; however, the majority of trials failed to adhere to these guidelines. Due to the great heterogeneity and the lack of important information regarding the standardization and content of herbal interventions, it appears that the evidence is not enough to secure a direction of effect for any of the examined outcomes.
34659225 Proton Pump Inhibitors Increase the Risk of Autoimmune Diseases: A Nationwide Cohort Study 2021 BACKGROUND: Previous study revealed proton pump inhibitors (PPIs) have an effect on gut microbiota. Alteration of the microbiome causes changes of the host immune system and then induces the development of autoimmune diseases (ADs). This study aimed to explore the possible association between PPIs use and ADs. METHODS: This study was conducted using data from the Taiwan National Health Insurance Research Database in the period between 2002 and 2015. We performed multivariate and stratified analysis through the Kaplan-Meier method and Cox proportional hazard models to estimate the association between proton pump inhibitor use and the risk of autoimmune diseases. RESULTS: Of the 297,099 patients treated with PPI identified, the overall mean (SD) age was 49.17 (15.63) years and 56.28% of the subjects was male. As compared with the non-PPI group, the adjusted hazard ratio (aHR) were higher for incident organ specific ADs such as Graves disease (aHR=3.28), Hashmoto thyroiditis (aHR=3.61), autoimmune hemolytic anemia (aHR=8.88), immune thrombocytopenic purpura (aHR=5.05) Henoch-Schonlein pupura (aHR=4.83) and Myasthenia gravis (aHR=8.73). Furthermore, the adjusted hazard ratio (aHR) were also higher for incident systemic ADs such as ankylosing spondylitis (aHR=3.67), rheumatoid arthritis (aHR=3.96), primary Sjogren syndrome (aHR=7.81), systemic lupus erythemtoasus (aHR=7.03). systemic vasculitis (aHR=5.10), psoriasis (aHR=2.57), systemic scleroderma (aHR=15.85) and inflammatory myopathy (aHR=37.40). Furthermore, we observed no dose-dependent effect between PPI use and the risk of ADs. CONCLUSIONS: Our retrospective population-based cohort study showed that the prescription of proton pump inhibitors is associated with a higher risk of ADs.
34651481 [Short-term effectiveness of novel computer navigation system assisted total knee arthropl 2021 Oct 15 OBJECTIVE: To investigate the short-term effectiveness of novel computer navigation system (Knee 3 software; Brainlab, Germany) assisted total knee arthroplasty (TKA). METHODS: Between July 2020 and December 2020, 19 patients underwent unilateral TKA assisted with Knee 3 software. There were 4 males and 15 females. The mean age was 66.3 years (range, 52-79 years). Eighteen patients were diagnosed with osteoarthritis and 1 patient with rheumatoid arthritis. Sixteen patients had varus knees and 3 patients had valgus knees. Preoperative Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain, stiffness, function, and total scores were 12.4±3.4, 2 (1, 4), 22 (18, 29), and 37 (29, 43), respectively. Intraoperatively, the medial and lateral gaps in knee extension and in 90° of knee flexion were recorded. The operation time, intraoperative blood loss, blood transfusion, and complications were recorded. The hip-knee-ankle angle (HKA), lateral distal femoral angle, and medial proximal tibial angle were measured to evaluate lower limb alignment and prostheses's alignment using X-ray films at 6 weeks after operation. Patient's satisfaction rate and WOMAC pain, stiffness, function, and total scores were investigated. RESULTS: Eighteen patients (94.7%) had medial- lateral gap balancing in knee extension, 18 patients (94.7%) had medial-lateral gap balancing in 90° of knee flexion, 19 patients (100%) had medial gap balancing between knee extension and 90° of knee flexion, and 18 patients (94.7%) had lateral gap balancing between knee extension and 90° of knee flexion. The mean operation time was 126 minutes (range, 100-200 minutes). The mean intraoperative blood loss was 205 mL (range, 100-400 mL). Patients were followed up 4-8 months, with an average of 6.2 months. Postoperative complications included 1 deep vein thrombosis of lower extremities and 1 cerebral infarction. X-ray films showed that the mean HKA, lateral distal femoral angle, and medial proximal tibial angle were 179.8° (range, 178°-182°), 83.5° (range, 80°-87°), and 89.5° (range, 87°-93°), respectively. At last follow-up, WOMAC pain, stiffness, function, and total scores were 3.6±1.9, 0 (0, 2), 4 (2, 6), and 9 (5, 10), respectively, which improved when compared with preoperative scores ( P<0.05). Twelve patients were very satisfied with the operation results and 7 patients were satisfied with the operation results. The overall satisfaction rate was 100%. CONCLUSION: Knee 3 software can help to obtain good gap balancing and optimal lower limb alignment, with high patient's satisfaction and good short-term effecectiveness.
34575178 A Pilot Study: Hypertension, Endothelial Dysfunction and Retinal Microvasculature in Rheum 2021 Sep 9 BACKGROUND: The etiology of autoimmune rheumatic diseases is unknown. Endothelial dysfunction and premature atherosclerosis are commonly seen in these patients. Atherosclerosis is considered one of the main causes of cardiovascular diseases. Hypertension is considered the most important traditional cardiovascular risk. This case-control study aimed to investigate the relationship between autoimmune diseases and cardiovascular risk. METHODS: This study was carried out in patients with rheumatoid arthritis, RA (n = 10), primary Sjögren syndrome, PSS (n = 10), and healthy controls (n = 10). Mean blood pressure (MBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse wave velocity (PWV, an indicator of arterial stiffness) were assessed via a Vicorder device. Asymmetric dimethylarginine (ADMA) was measured via ELISA. Retinal photos were taken via a CR-2 retinal camera, and retinal microvasculature analysis was carried out. T-tests were conducted to compare the disease and control groups. ANOVA and ANOVA-ANCOVA were also used for the correction of covariates. RESULTS: A high prevalence of hypertension was seen in RA (80% of cases) and PSS (40% of cases) compared to controls (only 20% of cases). Significant changes were seen in MBP (RA 101 ± 11 mmHg; PSS 93 ± 10 mm Hg vs. controls 88 ± 7 mmHg, p = 0.010), SBP (148 ± 16 mmHg in RA vs. 135 ± 16 mmHg in PSS vs. 128 ± 11 mmHg in control group; p = 0.007), DBP (77 ± 8 mmHg in RA, 72 ± 8 mmHg in PSS vs. 67 ± 6 mmHg in control; p = 0.010 in RA compared to the controls). Patients with PSS showed no significant difference as compared to controls (MBP: p = 0.240, SBP: p = 0.340, DBP: p = 0.190). Increased plasma ADMA was seen in RA (0.45 ± 0.069 ng/mL) and PSS (0.43 ± 0.060 ng/mL) patients as compared to controls (0.38 ± 0.059 ng/mL). ADMA in RA vs. control was statistically significant (p = 0.022). However, no differences were seen in ADMA in PSS vs. controls. PWV and retinal microvasculature did not differ across the three groups. CONCLUSIONS: The prevalence of hypertension in our cohort was very high. Similarly, signs of endothelial dysfunction were seen in autoimmune rheumatic diseases. As hypertension and endothelial dysfunction are important contributing risk factors for cardiovascular diseases, the association of hypertension and endothelial dysfunction should be monitored closely in autoimmune diseases.
34056884 Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine (PEA+ALC F 2021 Aug BACKGROUND: The neurologic complications of rheumatic diseases (RDs) are highly variable, and their manifestations are linked to the pathogenesis and clinical phenotype of the specific RDs. In rheumatoid arthritis, for example, the peripheral nervous system is most commonly involved and mononeuritis multiplex, nerve entrapment and vasculitic sensorimotor neuropathies are not uncommon. Often the therapy for these disorders is not easy and is characterized by the use of different drugs. Palmitoylethanolamide (PEA) has been tested in a wide variety of animal models and has been evaluated in several clinical studies for nerve compression syndromes, demonstrating that PEA acts as an effective and safe analgesic compound. Acetyl-L-Carnitine (ALC) has also been shown to be an effective and safe treatment in painful peripheral neuropathy. In the last years the synergistic effect between PEA and ALC has been demonstrated. The aim of our study was to evaluate the efficacy of supplementation of standard therapy (STh) with Kalanit(®) (Chiesi Italia Spa; Parma, Italy) in patients with peripheral neuropathy secondary to RDs. METHODS: Patients at the time of enrollment were affected by RDs with neuropathy from <12 months, documented by electromyography. The analyzed patients were treated with the STh chosen according to their rheumatic disease (RA or SpA) and for their neuropathy (e.g. analgesic, NSAIDs, pregabalin or gabapentin) as per clinical practice. The sample was divided into 2 groups: group 1, patients treated with STh, to which a fixed combination of PEA (600 mg) + ALC (500 mg) (Kalanit(®)) was added twice a day for 2 weeks and then once a day for 6 months; group 2, patients treated only with STh. Each patient underwent clinical evaluations and questionnaires were administered in order to evaluate their neuropathy and the efficacy of the therapy. RESULTS: In group 1, 18 patients suffering from sciatic pain, 16 patients from carpal tunnel syndrome and 8 patients with peripheral neuropathy of the lower limbs were included and PEA + ALC FC was added to STh. These patients were compared with patients from group 2, who had the same pathology and demographic characteristics: 20 patients with sciatic pain, 15 with carpal tunnel syndrome and 5 with peripheral neuropathy of the lower limbs, respectively; this group was treated with STh only. Patients treated with PEA + ALC FC had a significant improvement in pain VAS compared to patients treated with group 2 in all the diseases analyzed (P value: sciatic pain 0.032, carpal tunnel syndrome 0.025 and lower limbs neuropathy 0.041). Patients in group 1 showed a significant improvement compared to patients treated in group 2 also from a specific score. Specifically, LBP-IQ showed significant improvement in group one (P value: 0.031), as did CHFD (P=0.011) and NPQ (P=0.025). CONCLUSIONS: The synergistic effect of PEA and ALC seems to have a further advantage in the treatment of this type of pathology, including the anti-inflammatory effect but also in terms of therapy optimization and therefore of better adherence to treatments. Our study shows that it is important to identify the type of pain to follow an accurate diagnostic algorithm, considering the clinical characteristics of the patient and carefully evaluate the indication, preferring a multimodal approach.
34044135 The physical and mental burden of dry eye disease: A large population-based study investig 2021 Jul PURPOSE: This large cross-sectional population-based study investigated the relationship between dry eye disease (DED) and health-related quality of life (HR-QoL). METHODS: Dry eye and HR-QoL were assessed in 78,165 participants (19-94 yrs, 59.2% female) from the Dutch population-based Lifelines cohort, using the WHS and the SF36 questionnaire, respectively. Logistic regression was used to assess the relationship between DED and below median Physical Component Summary (PCS) and Mental Component Summary (MCS) score, corrected for age, sex, education, BMI, and 52 comorbidities. RESULTS: Overall, 8.9% of participants had DED. Participants with DED had an increased risk of low PCS (OR 1.54 (95% CI 1.46-1.62)) and MCS scores (OR 1.39 (95% CI 1.32-1.46)), corrected for age and sex. This risk remained significant after correction for comorbidities (P < 0.0005). Increasing DED symptom frequency was associated with decreasing HR-QoL (P < 0.0005). Undiagnosed DED subjects had a significantly increased risk of low mental HR-QoL with increasing dry eye symptoms compared to diagnosed subjects (P < 0.0005). Compared to allergic conjunctivitis, glaucoma, macular degeneration and retinal detachment, DED showed the highest risk of low HR-QoL. Compared to other common systemic and chronic disorders, such as depression, rheumatoid arthritis, and COPD, DED was distinctive by having a substantial reduction in both PCS and MCS. CONCLUSION: DED is associated with substantial reductions in both physical and mental HR-QoL, also after correction for associated comorbidities. Not having a diagnosis is associated with worse mental HR-QoL in subjects with severe DED. Our results underline the importance of recognizing dry eye as a serious disorder.
33932253 Discovery of K(V) 1.3 ion channel inhibitors: Medicinal chemistry approaches and challenge 2021 Jul The K(V) 1.3 voltage-gated potassium ion channel is involved in many physiological processes both at the plasma membrane and in the mitochondria, chiefly in the immune and nervous systems. Therapeutic targeting K(V) 1.3 with specific peptides and small molecule inhibitors shows great potential for treating cancers and autoimmune diseases, such as multiple sclerosis, type I diabetes mellitus, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis. However, no K(V) 1.3-targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K(V) 1.3 peptide and small-molecule inhibitors, and strategies to improve the selectivity of active compounds toward K(V) 1.3. Selectivity of dalatazide (ShK-186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases. Other peptides and small-molecule inhibitors are critically evaluated for their lead-like characteristics and potential for progression into clinical development. Some small-molecule inhibitors with well-defined structure-activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K(V) 1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K(V) 1.3 modulators against this target in the future.
33932202 Comparison of methods to improve fracture risk assessment in chinese diabetic postmenopaus 2021 Jul PURPOSE: This study evaluated the predictive power of adjusted FRAX and standard FRAX models based on the actual prevalence of osteoporosis in type 2 diabetic (T2DM) postmenopausal women, and to explore the optimal strategy to better predicted fracture risk in postmenopausal women with diabetes in China. METHODS: We recruited 434 patients from community-medical centers, 217 with T2DM and 217 without T2DM (non-T2DM). All participants completed self-reported questionnaires detailing their characteristics and risk factors. Bone mineral density (BMD) and spinal radiographs were evaluated. The China FRAX model calculated all scores. The area under the receiver operator characteristic curve (ROC-AUC) evaluated the sensitivity, specificity, and accuracy for predicting 10-year risk for major (MOF) and hip (OHF) osteoporotic fractures in T2DM patients. RESULTS: T2DM patients had higher BMD but lower average FRAX values than non-T2DM patients. The unadjusted FRAX ROC-AUC was 0.774, significantly smaller than that for 0.5-unit femoral neck T-score-adjusted FRAX (0.800; p = 0.004). Rheumatoid arthritis (RA; AUC = 0.810, p = 0.033) and T-score (AUC = 0.816, p = 0.002) adjustments significantly improved fracture prediction in T2DM patients. CONCLUSIONS: Femoral neck T-score adjustment might be the preferred method for predicting MOF and OHF in Chinese diabetic postmenopausal women, while RA adjustment only effectively predicted HF risk.
33846931 CTHRC1 Knockdown Promotes Inflammatory Responses Partially by p38 MAPK Activation in Human 2021 Oct Collagen triple helix repeat containing 1 (CTHRC1), a secreted glycoprotein, is widely expressed in many tissues. It has been recently defined as a novel marker for rheumatoid arthritis (RA), a systemic inflammatory disorder. However, the precise role of CTHRC1 in other chronic inflammatory diseases, like periodontal disease, remains unclear. This research aimed to explore the presence of CTHRC1 in periodontal inflammation, determine the precise role in inflammatory response modulation in periodontal ligament cells (PDLCs), and explore its underlying mechanisms. In vivo gingival crevicular fluid (GCF) and gingivae were obtained from healthy people and chronic periodontitis patients. Maxillary tissues of mice with or without ligature-induced periodontitis were immunostained for CTHRC1. In vitro human PDLCs were treated with tumor necrosis factor alpha (TNF-α) to mimic the inflammatory environment. Small interfering RNA (siRNA) was used to silence CTHRC1. SB203580 was used to inhibit the p38 mitogen-activated protein kinase (MAPK) pathway. CTHRC1 was highly expressed in GCF and gingival tissues of periodontitis patients. Animal models also revealed the same tendency. CTHRC1 knockdown promoted inflammatory cytokine production and activated the p38 MAPK signaling pathway in PDLCs. Inhibiting the p38 MAPK signaling pathway partially attenuated the inflammatory responses. This study revealed that CTHRC1 was highly expressed in periodontitis and suggested that CTHRC1 might play an important role in modulating periodontal inflammation.
33271118 Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK(+) CD8(+) T Cells as 2021 Jan 12 Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8(+) T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK(+)CD8(+) T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK(+) Taa cells as a potential target to address age-associated dysfunctions of the immune system.
33057917 QuantiFERON®-TB Gold In-Tube test can be used for screening latent tuberculosis before bi 2021 May OBJECTIVES: The Turkish population is vaccinated with Bacille Calmette-Guérin (BCG), and the BCG vaccination decreases the specificity of the tuberculin skin test (TST). The purpose of this study was to investigate the incidence of active tuberculosis (TBC) among rheumatic patients who were screened only with the QuantiFERON®-TB Gold In-Tube (QFT-GIT) test for latent TBC prior to biological treatment. METHODS: The Hacettepe University Biological Database (HUR-BIO) was used for latent TBC assessment. Consecutive patients were evaluated from July 2015 to October 2016 by a questionnaire that included the patients' demographic characteristics, treatment history, and symptoms of active TBC. A total of 664 patients were interviewed by physicians. TBC statuses of the 671 non-interviewed patients were checked from the Turkish National Tuberculosis Registry records. Mean TBC incidence per year was calculated for anti-tumor necrosis factor-alpha (TNF-α) agents. RESULTS: A total of 1335 (58.2% female) patients with the mean age of 44.2 ± 12.9 years were included. Of the patients, 836 (62.6%) had spondyloarthropathy, 432 (32.4%) had rheumatoid arthritis, and 67 (5%) had other rheumatologic diseases. The total biological drug exposure was 2292 patient-years (2043 patient-years for anti-TNF-α, 249 patient-years for non-TNF-α inhibitors). Positive and indeterminate QFT-GIT results were found in 258 (19.3%) and 23 (1.7%) patients, respectively. The median follow-up time after the onset of biological agent was 19.4 months (IQR = 29.5). Pulmonary TBC was found in 3 (0.2%) of the 1335 patients. The annual incidence of TBC was 147/100,000 patient-years for all TNF-α inhibitors (249/100,000 and 123/100,000 patient-years for QFT-GIT-positive and negative patients, respectively). CONCLUSIONS: TBC incidence increased by nearly seven times the Turkish national TBC incidence. The QFT-GIT Test appears acceptable to determine latent TBC before biological agent use. Consequently, the QFT-GIT Test can be appropriately used in BCG-vaccinated countries. Key Points • Our study contributes to filling the gap in the literature by reflecting real-life data about TBC frequency after QFT-GIT use in patients receiving biological agents. • The frequency of active TBC will remain within acceptable limits when only QFT-GIT is used in the screening of latent TBC prior to the use of biological agents in a population where the majority are vaccinated with BCG. • Using the QFT-GIT alone for latent TBC screening prior to biologic treatment in countries with high BCG vaccination rates reduces the number of patients needing isoniazid (INH) treatment.
32960100 Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose. 2021 Jan INTRODUCTION: While chloroquine, a derivative of quinine, has been used as an antimalarial for 70 years, hydroxychloroquine is now used to treat conditions such as rheumatoid arthritis and systemic lupus erythematosus. In 2020, hydroxychloroquine (and to a lesser extent chloroquine) also received attention as a possible treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During investigation for treating coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, concerns for serious adverse events arose. OBJECTIVE: We review the toxicity associated with hydroxychloroquine and chloroquine use both short-term and long-term and in overdose. METHODS: Medline (via OVID) was searched from its inception through June 7 2020 using the following as either MeSH or keyword terms: ("Chloroquine/" or "Hydroxychloroquine/") AND ("Adverse Drug Event/" or "Toxicities, Drug/" or "Toxic.mp." or "Toxicity.mp." or "Overdose.mp."). We limited resultant articles to those published in English and reporting on Human subjects. This search yielded 330 articles, of which 57 were included. Articles were excluded due to lack of relevance, not reporting desired outcomes, or being duplicative in their content. Twenty-five additional articles were identified through screening references of included articles. To identify toxicities in individuals treated with hydroxychloroquine or chloroquine with COVID-19, we searched PubMed on June 10th, 2020: ("Chloroquine" or "Hydroxychloroquine") AND ("Coronavirus" or "COVID-19" or "SARS-CoV-2"). This search resulted in 638 articles. We reviewed articles for reporting of adverse events or toxicities. Most citations were excluded because they did not include original investigations or extrapolated data from subjects that did not have COVID-19; 34 citations were relevant. For the drug-interactions section, relevant classes and agents were identified through a screen of the https://www.covid19-druginteractions.org/ website. We then conducted targeted searches of PubMed up to June 7th 2020 combining "chloroquine" and "hydroxychloroquine" with terms for specific drug classes and drugs identified from the drug-interaction site as potentially relevant. We found 29 relevant articles. TOXICITY WITH SHORT-TERM USE: Gastrointestinal: Gastrointestinal toxicities are the most common to occur following initiation of chloroquine or hydroxychloroquine. Nausea, vomiting, and diarrhea account for most reported intolerances. Glucose abnormalities: Alterations in blood glucose concentrations may occur with hydroxychloroquine but are rare with standard therapeutic use. Cardiotoxicity: Short-term use can produce conduction abnormalities. Evidence from COVID-19 treatment suggests QT/QTc prolongation is of concern, particularly when used in combination with azithromycin, although disagreement exists across studies. Dermatologic: Drug eruptions or rashes, followed by cutaneous hyperpigmentation, pruritis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, may occur within days to weeks of exposure but usually resolve with the discontinuation of therapy. Neuropsychiatric: Reported symptoms include confusion, disorientation, and hallucination within 24-48 h of drug initiation. Other toxicities: Hemolysis and anemia may occur in patients with glucose-6-phosphate dehydrogenase. Chloroquine treatment of COVID-19 was associated with elevation in creatine kinase and creatine kinase-MB activities with more events in the higher-dose group. TOXICITY WITH LONG-TERM USE: Retinopathy: Retinopathy is the major dose-limiting toxicity associated with long-term use; the risk is higher with increasing age, dose, and duration of usage. Cardiotoxicity: Long-term use has been associated with conduction abnormalities, cardiomyopathy, and valvular disorders. Neurotoxicity: Rarely myositis and muscle weakness, extremity weakness, and pseudoparkinsonism have been reported. TOXICITY IN OVERDOSE: Symptoms in overdose manifest rapidly (minutes to hours) and cardiotoxicity such as cardiovascular shock and collapse are most prominent. Neurotoxic effects such as psychosis and seizure may also occur. CONCLUSIONS: Hydroxychloroquine is a generally well-tolerated medication. Short-term (days to weeks) toxicity includes gastrointestinal effects and rarely glucose abnormalities, dermatologic reactions, and neuropsychiatric events. Cardiotoxicity became of increased concern with its use in COVID-19 patients. Long-term (years) toxicities include retinopathy, neuromyotoxicity, and cardiotoxicity (conduction abnormalities, cardiomyopathy). Deaths from overdoses most often result from cardiovascular collapse.
31639851 Comparison of Patient Demographics and Utilization Trends of Robotic-Assisted and Non-Robo 2021 May Robotic-assisted unicompartmental knee arthroplasty (RAUKA) is an emerging area of interest. The purpose of this study was to compare (1) different patient demographic profiles; (2) annual primary and revision utilization rates; (3) risk factors for revision procedures; and (4) survivorship between RAUKA and manual UKA (MUKA). Using the PearlDiver database, patients who underwent RAUKA or MUKA between 2005 and 2014 within the Medicare database were identified, yielding a total of 35,061 patients (RAUKA = 13,617; manual = 21,444). Patient demographics (age, gender, comorbidities, Charlson-Comorbidity Index, and geographic region) were compared between cohorts. Annual primary and revision utilization rates as well as risk factors for revision procedures were also compared. Kaplan-Meier survivorship was also calculated. The Pearson χ(2) test was used to test for significance in patient demographics, whereas the Welch t-test was used to compare the incidence of revisions as well as the revision burden (proportion of revisions to total sum of primary and revision procedures). Multivariate binomial logistic regression analysis was performed to compare risk factors for revision procedures. There were statistically significant differences in RAUKA versus MUKA patients with respect to age (p < 0.001), gender (p < 0.001), and region (p < 0.001). RAUKA procedures performed increased over 12-fold compared with manual, which increased only 4.5-fold. RAUKA procedures had significantly lower revision incidence (0.99 vs. 4.24%, p = 0.003) and revision burden (0.91 vs. 4.23%, p = 0.005) compared with manuals. For patients undergoing RAUKA, normal (19-24 kg/m(2)) and obese (30-39 kg/m(2)) body mass index (p < 0.05), congestive heart failure (p = 0.004), hypothyroidism (p < 0.001), opioid dependency (p = 0.002), and rheumatoid arthritis (p < 0.001) were risk factors for a revision procedure. Kaplan-Meier survival curve 3 years following the index procedure to all-cause revisions demonstrated that RAUKA patients maintained nearly 100% survivorship compared with manual patients who had 97.5% survivorship. The data demonstrate increased utilization of RAUKA in the United States. The current data indicated that RAUKA has significantly lower revision rates and improved survivorship compared with patients undergoing non-RAUKA within Medicare patients.
35011118 Paratuberculosis: The Hidden Killer of Small Ruminants. 2021 Dec 21 Paratuberculosis (PTB) is a contagious and chronic enteric disease of ruminants and many non-ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP), and is characterised by diarrhoea and progressive emaciation with consequent serious economic losses due to death, early culling, and reduced productivity. In addition, indirect economic losses may arise from trade restrictions. Besides being a production limiting disease, PTB is a potential zoonosis; MAP has been isolated from Crohn's disease patients and was associated with other human diseases, such as rheumatoid arthritis, Hashimoto's thyroiditis, Type 1 diabetes, and multiple sclerosis. Paratuberculosis in sheep and goats may be globally distributed though information on the prevalence and economic impact in many developing countries seem to be scanty. Goats are more susceptible to infection than sheep and both species are likely to develop the clinical disease. Ingestion of feed and water contaminated with faeces of MAP-positive animals is the common route of infection, which then spreads horizontally and vertically. In African countries, PTB has been described as a "neglected disease", and in small ruminants, which support the livelihood of people in rural areas and poor communities, the disease was rarely reported. Prevention and control of small ruminants' PTB is difficult because diagnostic assays demonstrate poor sensitivity early in the disease process, in addition to the difficulties in identifying subclinically infected animals. Further studies are needed to provide more insight on molecular epidemiology, transmission, and impact on other animals or humans, socio-economic aspects, prevention and control of small ruminant PTB.
34442026 Serum Amphiregulin and Heparin-Binding Epidermal Growth Factor as Biomarkers in Patients w 2021 Aug 22 BACKGROUND: The epidermal growth factors amphiregulin (AREG) and heparin-binding epidermal growth factor (HB-EGF) are implicated in the pathogenesis of several autoimmune diseases, but their clinical and pathological roles in idiopathic inflammatory myopathy (IIM) are unclear. METHODS: Serum AREG and HB-EGF levels were measured by ELISA in patients with IIM (n = 37), systemic sclerosis (n = 17), and rheumatoid arthritis (n = 10), and for seven age- and sex-matched healthy controls (HCs). Associations between serum AREG or HB-EGF levels and the clinical parameters were analyzed. RESULTS: Serum AREG levels in IIM patients were significantly elevated compared to those in HCs (median, 20.7 and 10.7 pg/mL, respectively; p = 0.025). In particular, serum AREG levels in IIM patients with interstitial lung disease (ILD) were higher than those of HCs (22.4 pg/mL, p = 0.027). The disease duration in patients with elevated serum AREG levels was significantly shorter compared to those who had normal serum AREG levels (7 and 21 months, respectively; p = 0.0012). Serum HB-EGF levels were significantly increased in IIM patients with elevated CK levels (136.2 pg/mL; p = 0.020) and patients with anti-Mi-2 antibody (183.7 pg/mL; p = 0.045) compared to those in HCs (74.9 pg/mL). CONCLUSION: These results suggested that AREG could be a promising biomarker associated with early-phase IIM-related ILD, and that HB-EGF expression was associated with muscle injury and regeneration in IIM.