Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S.

During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells' increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment.

The Risk of Herpes Zoster Events in Patients with Spondyloarthritis and the Effect of BNT162b2 mRNA COVID-19 Vaccine.

The data on the risk of herpes zoster (HZ) in spondyloarthropathy (SpA) patients are sparse, especially regarding its association with the novel mRNA COVID-19 vaccines and immunosuppressants. We aimed to evaluate whether SpA diagnosis and/or immunosuppressant use affect HZ risk and the influence of mRNA COVID-19 vaccination. We assessed the association between SpA (psoriatic arthritis (PsA) and ankylosing spondylitis (AS)) diagnoses and HZ in a large population database with patients matched by age and sex to controls. We also assessed the association between the COVID-19 vaccine and new-onset HZ using two nested case-control studies, identifying all new HZ cases diagnosed from 1 January-31 December 2021 within the SpA and general population cohorts, matched randomly by sex, age and HZ index date to controls without HZ. Exposure to mRNA COVID-19 vaccination was ascertained in the 6 weeks prior to the index date both in cases and controls. In our results, the incidence rate of HZ was higher in PsA patients vs. the general population, at 1.03 vs. 0.64 per 100 person-years, respectively (adjusted HR = 1.55; 95%CI, 1.19-2.02). Within the SpA group, Jak-I treatment was associated with a higher risk of developing new-onset HZ (adjusted OR = 3.79; 1.15-12.5). Multivariable conditional logistic regression models we used showed no association between COVID-19 vaccination and new-onset HZ among the SpA patients (OR = 1.46; 0.68-3.14).

The risk factors for uveitis among psoriatic arthritis patients: a population-based cohort study.

OBJECTIVE: To assess the frequency of uveitis in patients with psoriatic arthritis (PsA) in the era of biologics and to identify risk factors associated with uveitis. METHODS: A retrospective matched cohort study was conducted within the database of a large healthcare provider. Newly diagnosed 6147 adult PsA patients between 2005 and 2020 were matched by the index date of PsA diagnosis, age, sex, and ethnicity to 23,999 randomly selected controls. This cohort was used to examine the association between PsA and uveitis. An additional analysis was conducted within the PsA group to identify uveitis risk factors, using two analytic approaches: a retrospective cohort study and a nested case-control study. RESULTS: Uveitis was diagnosed in 107 patients in the PsA group (1.7%) vs 187 (0.8%) patients in the control group (adjusted HR, 2.38, 95% CI 1.80-3.15, p<0.005) and was similar when the analysis was confined to patients without past uveitis. Uveitis was diagnosed more in females (2.1% vs 1.3%, HR 1.61, 95% CI 1.09-2.40, p<0.05), and was acute in all cases. Anterior uveitis was documented in 41.1% of the cases, 64.5% unilateral, and 9.3% bilateral. In the PsA group, using nested case control approach, only past uveitis [adjusted OR 136.4 (95% CI 27.38-679.88), p<0.005] and treatment with etanercept [adjusted OR 2.57 (95% CI 1.45-4.57), p=0.001] were independently associated with uveitis. Only one PsA patient with uveitis (out of 107) required systemic oral treatment with prednisone, while the rest of the patients were treated with topical glucocorticosteroids only. CONCLUSION: PsA is associated with increased risk of uveitis. Past uveitis and treatment with etanercept were associated with higher risk of uveitis. Key Points • Psoriatic arthritis (PsA) is a major risk factor for uveitis with hazard ratio of 2.38 compared to healthy individuals without PsA. • Among PsA patients, the past event of uveitis and treatment with etanercept are risk factors for uveitis. • Uveitis in patients treated with biologics for their PsA requires topical therapy only in most of the cases.

Real-Life Utilization of Criteria Guidelines for Diagnosis of Cardiac Sarcoidosis (CS).

Despite the increasing recognition of cardiac involvement in systemic sarcoidosis, the diagnosis of cardiac sarcoidosis (CS) remains challenging. Our aim is to present a comprehensive, retrospective case series of CS patients, focusing on the current diagnostic guidelines and management of this life-threatening condition. In our case series, patient data were collected retrospectively, including hospital admission records and rheumatology and cardiology clinic visit notes, detailing demographic, clinical, laboratory, pathology, and imaging studies, as well as cardiac devices and prescribed medications. Cases were divided into definite and probable CS based on the 2014 Heart Rhythm Society guidelines as well as presumed CS based on imaging criteria and clinical findings. Overall, 19 CS patients were included, 17 of whom were diagnosed with probable or presumed CS based on cardiac magnetic resonance imaging (CMR) and/or cardiac positron emission tomography using 18F-Fluorodeoxyglucose (PET-FDG) without supporting endomyocardial biopsy (EMB). The majority of CS patients were male (53%), with a mean age of 52.9 ± 11.8, with CS being the initial manifestation of sarcoidosis in 63% of cases. Most patients presented with high-grade AVB (63%), followed by heart failure (42%) and ventricular tachyarrhythmia (VT) (26%). This case series highlights the significance of utilizing updated diagnostic criteria relying on CMR and PET-FDG given that cardiac involvement can be the initial manifestation of systemic sarcoidosis, requiring prompt diagnosis and treatment to prevent morbidity and mortality.

Implementation of Calcium and Vitamin D Supplementation in Glucocorticosteroid-Induced Osteoporosis Prevention Guidelines-Insights from Rheumatologists.

Glucocorticosteroid-induced osteoporosis (GIO) is the most common cause of secondary osteoporosis but is underdiagnosed and undertreated. Our aim in this communication is to review the literature on the implementation of current GIO prevention practices such as calcium and vitamin D supplementation with emphasis on the rheumatologists' perspective relating to the need for development of novel GIO educational prevention measures.

A deep look into the storm: Israeli multi-center experience of coronavirus disease 2019 (COVID-19) in patients with autoimmune inflammatory rheumatic diseases before and after vaccinations.

Objective: We aimed to characterize the course of COVID-19 in autoimmune inflammatory rheumatic disease (AIIRD) patients in Israel, taking into consideration several remarkable aspects, including the outcomes of the different outbreaks, the effect of vaccination campaigns, and AIIRD activity post-recovery. Methods: We established a national registry of AIIRD patients diagnosed with COVID-19, including demographic data, AIIRD diagnosis, duration and systemic involvement, comorbidities, date of COVID-19 diagnosis, clinical course, and dates of vaccinations. COVID-19 was diagnosed by a positive SARS-CoV-2 polymerase chain reaction. Results: Israel experienced 4 outbreaks of COVID-19 until 30.11.2021. The first three outbreaks (1.3.2020 - 30.4.2021) comprised 298 AIIRD patients. 64.9% had a mild disease and 24.2% had a severe course; 161 (53.3%) patients were hospitalized, 27 (8.9%) died. The 4th outbreak (delta variant), starting 6 months after the beginning of the vaccination campaign comprised 110 patients. Despite similar demographic and clinical characteristics, a smaller proportion of AIIRD patients had negative outcomes as compared to the first 3 outbreaks, with regards to severity (16 patients,14.5%), hospitalization (29 patients, 26.4%) and death (7 patients, 6.4%). COVID-19 did not seem to influence the AIIRD activity 1-3 months post-recovery. Conclusions: COVID-19 is more severe and has an increased mortality in active AIIRD patients with systemic involvement, older age and comorbidities. Vaccination with 3 doses of the mRNA vaccine against SARS-CoV-2 protected from severe COVID-19, hospitalization and death during the 4th outbreak. The pattern of spread of COVID-19 in AIIRD patients was similar to the general population.

Development of Autoantibodies Following BNT162b2 mRNA COVID-19 Vaccination and Their Association with Disease Flares in Adult Patients with Autoimmune Inflammatory Rheumatic Diseases (AIIRD) and the General Population: Results of 1-Year Prospective Follow-Up Study.

Development of autoantibodies following BNT162b2 mRNA COVID-19 vaccination and their association with disease flares in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and the general population: results of 1-year prospective follow-up study. We conducted a prospective study aimed at investigating the incidence of appearance of autoantibodies (antinuclear, antiphospholipid, and rheumatoid factor) in the sera of 463 adult patients with AIIRD compared to 55 controls from the general population prior to, and following the second and third vaccine doses, and at 1-year of follow-up. Pre- and post-vaccination disease activity indices and the association of autoantibodies with rheumatic disease flares and new onset AIIRD were examined. Autoantibody development of any type in AIIRD patients vs. the controls was 4.0% (vs. 6.7%, p = 0.423) following two vaccine doses and 7.6% (vs. 0%, p = 0.152) after three doses. There was no significant difference in sex, age, or disease-type among individuals with and without autoantibody development, regardless of the immunosuppressant use. More patients developed autoantibodies following the third than the second vaccine dose (p = 0.004). Disease flares occurred in 5.8% and 7.2% of AIIRD patients following second and third vaccine doses, respectively, with autoantibody production increasing the risk of flares following the second (p = 0.002) and third (p = 0.004) vaccine doses. BNT162b2 vaccination resulted in the development of autoantibodies in a minority of AIIRD patients and controls. Autoantibody development was associated with disease flares in patients, but no new-onset autoimmunity was observed.

Immunogenicity induced by two and three doses of the BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic diseases and immunocompetent controls: a longitudinal multicentre study.

OBJECTIVES: To evaluate long-term kinetics of the BNT162b2 mRNA vaccine-induced immune response in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and immunocompetent controls. METHODS: A prospective multicentre study investigated serum anti-SARS-CoV-2 S1/S2 IgG titre at 2-6 weeks (AIIRD n=720, controls n=122) and 6 months (AIIRD n=628, controls n=116) after the second vaccine, and 2-6 weeks after the third vaccine dose (AIIRD n=169, controls n=45). T-cell immune response to the third vaccine was evaluated in a small sample. RESULTS: The two-dose vaccine regimen induced a higher humoral response in controls compared with patients, postvaccination seropositivity rates of 100% versus 84.72%, p<0.0001, and 96.55% versus 74.26%, p<0.0001 at 2-6 weeks and at 6 months, respectively. The third vaccine dose restored the seropositive response in all controls and 80.47% of patients with AIIRD, p=0.0028. All patients treated with methotrexate monotherapy, anticytokine biologics, abatacept and janus kinase (JAK) inhibitors regained the humoral response after the third vaccine, compared with only a third of patients treated with rituximab, entailing a 16.1-fold risk for a negative humoral response, p≤0.0001. Cellular immune response in rituximab-treated patients was preserved before and after the third vaccine and was similar to controls. Breakthrough COVID-19 rate during the Delta surge was similar in patients and controls, 1.83% versus 1.43%, p=1. CONCLUSIONS: The two-dose BNTb262 regimen was associated with similar clinical efficacy and similar waning of the humoral response over 6 months among patients with AIIRD and controls. The third vaccine dose restored the humoral response in all of the controls and the majority of patients.

Predictors of Immunogenic Response to the BNT162b2 mRNA COVID-19 Vaccination in Patients with Autoimmune Inflammatory Rheumatic Diseases Treated with Rituximab.

Treatment with rituximab (RTX) blunts SARS-CoV-2 vaccination-induced humoral response. We sought to identify predictors of a positive immunogenic response to the BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic diseases (AIIRD) treated with RTX (AIIRD-RTX). We analyzed 108 AIIRD-RTX patients and 122 immunocompetent controls vaccinated with BNT162b2 mRNA participating in a multicenter vaccination study. Immunogenicity was defined by positive anti-SARS-CoV-2 S1/S2 IgG. We used a stepwise backward multiple logistic regression to identify predicting factors for a positive immunogenic response to vaccination and develop a predicting calculator, further validated in an independent cohort of AIIRD-RTX BNT162b2 mRNA vaccinated patients (n = 48). AIIRD-RTX patients who mounted a seropositive immunogenic response significantly differed from patients who did not by a lower number of RTX courses (median (range) 3 (1-10) vs. 5 (1-15), p = 0.007; lower cumulative RTX dose (mean ± SD) 6943.11 ± 5975.74 vs. 9780.95 ± 7240.12 mg, p = 0.033; higher IgG level prior to last RTX course (mean ± SD), 1189.78 ± 576.28 vs. 884.33 ± 302.31 mg/dL, p = 0.002), and extended interval between RTX treatment and vaccination, 469.82 ± 570.39 vs. 162.08 ± 160.12 days, p = 0.0009, respectively. Patients with ANCA-associated vasculitis and inflammatory myositis had a low likelihood of a seropositive immunogenic response compared to patients with rheumatoid arthritis, odds ratio (OR) 0.209, 95% confidence interval (CI) 0.046-0.96, p = 0.044 and OR 0.189, 95% CI 0.036-0.987, p = 0.048, respectively. Based on these findings, we constructed a calculator predicting the probability of a seropositive immunogenic response following BNT162b2 mRNA vaccination which performed with 90.5% sensitivity, 59.3% specificity, and 63.3% positive and 88.9% negative predictive values. In summary, the predicting calculator could guide clinicians for optimal timing of BNT162b2 mRNA vaccination in AIIRD-RTX patients.

The association between psoriatic arthritis and venous thromboembolism: a population-based cohort study.

BACKGROUND: Although the risk of cardiovascular disease has been discussed extensively in both psoriasis (PsO) and psoriatic arthritis (PsA), very few studies have addressed the occurrence of venous thromboembolic (VTE) events among PsO patients, and even fewer in PsA. Thus, our goal was to assess the association between PsA and VTE events using a large population-based database. METHODS: This retrospective cohort study includes all 5,275 patients with newly diagnosed PsA from the largest health care provider in Israel between January 2003 and December 2018. Identified PsA patients were matched by age, sex, ethnicity, and index date with 21,011 controls without PsA from the same database. Both groups were followed through June 30, 2019 for the occurrence of VTE event. Cox proportional hazard regression models were used to assess the association between PsA and VTE. RESULTS: PsA cohort consisted of 53.2% females with mean age of 51.7±15.4 Sixty-two patients (1.2%) were diagnosed with VTE in the PsA group and 176 patients (0.8%) in the control group (p=0.023, HR=1.40, 95% CI 1.05-1.87). However, there was no increased risk of VTE among PsA patients on multivariable analysis (p=0.16, HR=1.27, 95% CI 0.91-1.80). Within the PsA group, patients with VTE were more often of older age and with history of VTE. CONCLUSIONS: This study suggests that the increased risk of VTE in PsA patients appears to be related to the underlying comorbidities and not independently associated with PsA. Age and previous history of VTE were the only risk factors associated with increased risk of VTE in patients with PsA. Addressing VTE risk is recommended especially in the era of Janus kinase inhibitors.

The Association of Psoriatic Arthritis With All-cause Mortality and Leading Causes of Death in Psoriatic Arthritis.

OBJECTIVE: To examine the association between psoriatic arthritis (PsA) and all-cause mortality from a large population-based database. METHODS: Patients with PsA from the Clalit Health Services database were identified between 2003-2018 and matched to 4 controls by age, sex, ethnicity, and index date. Patient demographics, comorbidities, and treatments were extracted. Mortality data were obtained from the Israeli Notification of Death certificate. The proportionate mortality rate (PMR) of the leading causes of death was calculated and compared to that of the general population. Cox proportional hazard regression models were used to estimate the crude and the multivariate adjusted HR for the association between PsA and all-cause mortality and for factors associated with mortality within the PsA group. RESULTS: There were 5275 patients with PsA and 21,011 controls included and followed for 7.2 ± 4.4 years. The mean age was 51.7 ± 15.4 years, and 53% were females. Among patients with PsA, 38.2% were on biologics. Four hundred seventy-one (8.9%) patients died in the PsA group compared to 1668 (7.9%) in the control group. The crude HR for the association of PsA and all-cause mortality was 1.16 (95% CI 1.04-1.29) and 1.02 (95% CI 0.90-1.15) on multivariate analysis. Malignancy was the leading cause of death (26%), followed by ischemic heart disease (15.8%); this is in keeping with the leading causes of death in the general population. Older age, male sex, lower socioeconomic status, increased BMI, increased Charlson comorbidity index scores, and history of psoriasis or hospitalization in 1 year prior to entry were positive predictors for mortality. CONCLUSION: No clinically relevant increase in mortality rate was observed in patients with PsA, and specific PMRs were similar to those of the general population.

Implementation of the Treat-to-Target Concept in Evaluation of Psoriatic Arthritis Patients.

BACKGROUND: The treat-to-target approach was recently adopted for psoriatic arthritis (PsA) management. OBJECTIVE: To assess the implementation of the "treat-to-target" (T2T) concept in daily management of PsA by use of composite scores of disease activity versus clinical judgement alone. METHODS: A total of 117 PsA patients from a longitudinal PsA cohort were enrolled consecutively in the study during each patient's first clinic visit during 2016-2017. Clinic notes from the treating rheumatologist were reviewed by an independent rheumatologist, noting clinical impression of disease activity, treatment changes based on clinical judgement, and rationale. Treatment changes were then compared to the use of formal disease activity parameters in Minimal Disease Activity (MDA) and Disease Activity Index for Psoriatic Arthritis (DAPSA) composite measures. All associations were assessed using the chi-square test or the Mann-Whitney test, as appropriate. RESULTS: The 117 PsA patient cohort consisted of 65.5% women, mean age 58.4 ± 13.6 years. Clinical judgement of treating rheumatologist concorded with MDA and DAPSA in 76 (65.5%) and 74 (64.9%) patients, respectively. Agreement between clinical judgement and composite measure criteria did not correlate with patient age, sex, alcohol/tobacco use, or treatment regimens chosen. Disagreement between physician assessment and MDA occurred in 40 (34.5%) cases: in 30 cases, the MDA status was overestimated due to disregard of patient reported outcomes (PRO), while underestimation of MDA status occurred in 25% of cases with treatment changes made in patients with a single active joint or enthesis. Underestimation of disease activity using DAPSA occurred in 22 cases and could be attributed to disregarding tender joint count, patient pain visual analogue scale and C-reactive protein level. CONCLUSION: In our cohort, agreement between clinical impression and formal composite measure utilization for implementation of T2T strategy occurred in 65% of patients. Discordance resulted from physicians' overlooking PRO and emphasizing objective findings when using clinical judgement alone.

Treatment persistence of biologics among patients with psoriatic arthritis.

BACKGROUND: Persistence of biologic therapy in psoriatic arthritis (PsA) patients is an important factor in individualized patient treatment planning and healthcare policy and guideline development. OBJECTIVE: To estimate the persistence of biologic agents prescribed to PsA patients in a real-life setting as well as factors associated with improved biologic drug survival in these patients. METHODS: Patients with PsA from a large healthcare provider database with at least two consecutive dispensed prescriptions of a biologic agent indicated for PsA from January 1, 2002, until December 31, 2018, were identified and followed until medication stop date or the end of observation period. Patients were considered non-persistent whenever a permissible lag time of 6 months from the time of prescription issuance until medication filling date was exceeded. Treatment changes were based on physician decisions and patient preferences. Demographic data including age, sex, body mass index (BMI), ethnicity, smoking history, and socioeconomic status as well as Charlson comorbidity index were retrieved. Data regarding use of steroids and conventional disease-modifying anti-rheumatic drugs (cDMARDs) were also extracted. Descriptive statistics, including means (standard deviations) for continuous variables and frequencies (%) for categorical variables, were used. Persistence estimates were derived using non-parametric survival analysis using Kaplan-Meier functions, with treatment discontinuations as failure events. Cox regression hazard ratio models were conducted to investigate factors associated with drug persistence. RESULTS: A total of 2301 PsA patients with 2958 treatment periods were identified and included in the analyses. Mean age of the study population was 50.9 ± 14 years, 54% were females, 70.4% were with BMI > 25, 40% were current smokers, and 76% were with a Charlson comorbidity index > 1. The most commonly prescribed drug was etanercept (33%), followed by adalimumab (29%), golimumab (12%), secukinumab (10%), ustekinumab (8%), and infliximab (8%). While approximately 40% of patients persisted on therapy following 20 months of treatment, only about 20% of patients remained on any particular biologic agent after 5 years. Analyzing the data for all treatment periods while taking into account all lines of therapy revealed that secukinumab had a higher persistency than adalimumab, infliximab, and ustekinumab, with a log rank of 0.022, 0.047, and 0.001, respectively. Female sex and smoking were associated with lower drug persistence (HR = 1.25, 95% CI = 1.13-1.38 and HR = 1.109, 95% CI = 1.01-1.21, respectively). On analyzing the data using only the first indicated biologic line, no superiority of any single anti-tumor necrosis factor-alpha (anti-TNFα) agent was observed, while secukinumab was found to be superior as second line therapy to adalimumab, etanercept, infliximab, and ustekinumab but not to golimumab with a log rank P value of 0.001, 0.004, 0.025, and 0.002, respectively. CONCLUSIONS: In this large observational cohort studied in the era of biologic therapy, a relatively low drug persistence was observed, with female sex and smoking having a negative impact on persistency. None of the anti-TNFα agents was found to be more persistent than others as first line therapy, while secukinumab was found to be superior to other biologics when indicated as second line of therapy.

Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis Through Its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147.

Background: Angiogenesis is a major contributor to the development of inflammation during Rheumatoid arthritis (RA), as the vascularization of the pannus provides nutrients and oxygen for the infiltrating immune cells and proliferating synoviocytes. Tocilizumab (TCZ) is an anti-IL-6 receptor antibody that is used in the treatment of RA patients, and has been shown to exert anti-inflammatory effects. However, its effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown. Methods: We evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts (the HT1080 cell line) and monocytes (the U937 cell line) to explore the mechanisms of TCZ action. Results: Serum samples from RA patients treated with TCZ exhibited reduced circulating levels of EMMPRIN/CD147, enhanced expression of circulating miR-146a-5p and miR-150-5p, and reduced the angiogenic potential as was manifested by the lower number of tube-like structures that were formed by EaHy926 endothelial cell line. In vitro, the accumulation in the supernatants of the pro-angiogenic factors EMMPRIN, VEGF and MMP-9 was increased by co-culturing the HT1080 fibroblasts and the U937 monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 (Tsp-1) and the expression levels of miR-146a-5p were reduced. Transfection of HT1080 cells with the miR-146a-5p mimic, decreased the accumulation of EMMPRIN, VEGF and MMP-9. When we neutralized EMMPRIN with a blocking antibody, the supernatants derived from these co-cultures displayed reduced migration, proliferation and tube formation in the functional assays. Conclusions: Our findings implicate miR-146a-5p in the regulation of EMMPRIN and propose that TCZ affects angiogenesis through its effects on EMMPRIN and miR-146a-5p.

Increased Prevalence of Systemic Lupus Erythematosus Comorbidity in Patients With Psoriatic Arthritis: A Population-based Case-control Study.

OBJECTIVE: To assess the prevalence of systemic lupus erythematosus (SLE) in a psoriatic arthritis (PsA) cohort and to compare it to the general population using the database of a large healthcare provider. METHODS: We analyzed the database of a PsA cohort (2002-2017), matched for age and sex, with randomly selected controls for demographics, clinical and laboratory manifestations, and dispensed medications. Statistical analysis used t test and chi-square test as appropriate. In the PsA group, incidence density sampling was performed matching PsA patients without SLE as controls to each case of PsA with SLE by age and follow-up time. Univariable and multivariable conditional logistic regression analyses were used to assess factors affecting SLE development. RESULTS: The PsA and control groups consisted of 4836 and 24,180 subjects, respectively, with a median age of 56 ± 15 years, and of whom 53.8% were female. Eighteen patients (0.37%) in the PsA group and 36 patients (0.15%) in the control group were diagnosed with SLE (P = 0.001). SLE patients without PsA had higher anti-dsDNA and anticardiolipin antibodies. The usage of drugs with known potential to induce SLE was higher in the PsA than in the control group. Older age at PsA diagnosis, shorter PsA duration, and statin treatment were associated with SLE in PsA patients. CONCLUSION: A 2.3-fold increase in the prevalence of SLE in PsA relative to the control group was found. Risk factors for SLE development included older age at PsA diagnosis, shorter PsA duration, and statin treatment. The association between PsA and SLE may affect treatment choices and medication development.

The role of EMMPRIN/CD147 in regulating angiogenesis in patients with psoriatic arthritis.

BACKGROUND: Angiogenesis plays a central role in the pathophysiology of rheumatic diseases. Patients with psoriatic arthritis (PsA) demonstrate increased vascularity over patients with rheumatoid arthritis (RA), with unknown mechanisms. METHODS: We evaluated the serum levels of several pro- and anti-angiogenic factors in 62 PsA patients with active disease, 39 PsA patients in remission, 33 active RA patients, and 33 healthy controls (HC). Additionally, we used an in vitro co-culture system of fibroblast (HT1080) and monocytic-like (MM6) cell lines, to evaluate how their interactions affect the secretion of angiogenic factors and angiogenesis promoting abilities using scratch and tube formation assays. RESULTS: PsA patients, regardless of disease activity, exhibited higher levels of EMMPRIN/CD147, IL-17, and TNF-α relative to RA patients or HC. Factors, such as IL-6, and the ratio between CD147 and thrombospondin-1, exhibited elevated levels in active PsA patients relative to PsA patients in remission. Secretion of CD147, VEGF, and MMP-9 was increased in vitro. CD147 neutralization with an antibody reduced these levels and the ability of endothelial cells to form tube-like structures or participate in wound healing. CONCLUSIONS: CD147 plays a role in mediating angiogenesis in PsA, and the therapeutic possibilities of neutralizing it merit further investigation.

Polymyalgia Rheumatica: a Common Disease in Seniors.

PURPOSE OF THE REVIEW: Polymyalgia rheumatica (PMR) is one of the most common inflammatory rheumatologic condition occurring in older adults. It is characterized by proximal pain and stiffness in the shoulders, neck, and/or pelvic girdle in individuals over 50 years of age along with evidence of an intense systemic inflammatory response. Although the above clinical symptoms are very characteristic for the condition, it can be mimicked by other autoimmune, infectious, malignant, and endocrine disorders chief among which are giant cell arteritis (GCA) and elderly-onset rheumatoid arthritis (EORA). Recently, PMR was reported in relation to treatment with immune checkpoint inhibitors. Current treatment of PMR consists of low-to-medium doses of glucocorticosteroids (GC) with variable response rates and disease recurrence estimated to occur in 50% of patients while tapering down GC doses. In addition, GC-based regimens cause much of the morbidity associated with PMR in older adults, requiring close monitoring for GC-induced toxicity during therapy and highlighting the need for novel therapeutic strategies. Here, we review the latest findings in the field regarding specific etiologic factors, genetic associations, diagnostic methods, and advancements in treatment strategies and disease monitoring indices. RECENT FINDINGS: Recent discoveries involving novel therapeutic targets in GCA have accelerated the study of PMR pathophysiology and have advanced treatment strategies in PMR management leading to current trials in IL-6 blocking agents. PMR remains an enigmatic inflammatory condition affecting older adults, with current treatment approach causing much morbidity in this patient population. Advancements in our understanding of novel immunopathologic targets can serve as a solid foundation for future treatment strategies in the field.