Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S.

Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.

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.

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.

Herpes zoster following BNT162b2 mRNA COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series.

OBJECTIVES: As global vaccination campaigns against COVID-19 disease commence, vaccine safety needs to be closely assessed. The safety profile of mRNA-based vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is unknown. The objective of this report is to raise awareness of reactivation of herpes zoster (HZ) following the BNT162b2 mRNA vaccination in patients with AIIRD. METHODS: The safety of the BNT162b2 mRNA vaccination was assessed in an observational study monitoring post-vaccination adverse effects in patients with AIIRD (n = 491) and controls (n = 99), conducted in two rheumatology departments in Israel. RESULTS: The prevalence of HZ was 1.2% (n = 6) in patients with AIIRD compared with none in controls. Six female patients aged 49 ± 11 years with stable AIIRD: RA (n = 4), Sjogren's syndrome (n = 1), and undifferentiated connective disease (n = 1), developed the first in a lifetime event of HZ within a short time after the first vaccine dose in five cases and after the second vaccine dose in one case. In the majority of cases, HZ infection was mild, except a case of HZ ophthalmicus, without corneal involvement, in an RA patient treated with tofacitinib. There were no cases of disseminated HZ disease or postherpetic neuralgia. All but one patient received antiviral treatment with a resolution of HZ-related symptoms up to 6 weeks. Five patients completed the second vaccine dose without other adverse effects. CONCLUSION: Epidemiologic studies on the safety of the mRNA-based COVID-19 vaccines in patients with AIIRD are needed to clarify the association between the BNT162b2 mRNA vaccination and reactivation of zoster.

Cardiac and cardiovascular morbidities in patients with psoriatic arthritis: a population-based case control study.

OBJECTIVE: To assess the prevalence of risk factors associated with cardiovascular disease (CVD) and CVD-related morbidity in a large Middle-Eastern psoriatic arthritis (PsA) cohort. METHOD: A retrospective case control study was conducted using Israel's largest health care provider's patient database from 2000 to 2013. For each patient with PsA, 10 patients with no history of psoriasis or arthritis were matched for age and sex. Analysis of CVD-related risk factors and morbidity included hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus type 2 (DM-2), obesity, smoking, ischemic heart disease (IHD), congestive heart failure (CHF), cerebrovascular accident (CVA), carotid artery disease, peripheral vascular disease (PVD), aortic aneurism, valvular heart disease (VHD), and cardiomyopathy. Statistical analysis was conducted using t test and chi-square tests as appropriate. Univariate and multivariable logistic regression models assessed the association between PsA and CVD-related risk factors and morbidity. RESULTS: Three thousand one hundred sixty-one PsA patients were included, with average age 58 ± 15.0 years, of whom 53.4% were women. Increased prevalence of DM-2, HLD, HTN, and obesity (OR 1.7, 1.5, 1.5, 1.5 respectively) was noted in the PsA group. Increased prevalence of IHD (p < 0.0001), PVD (p < 0.0001), CHF (p = 0.002), VHD (p < 0.0001), and cardiomyopathy (p = 0.006) was found in the PsA group compared to the control group even after adjusting for CVD risk factors. CONCLUSIONS: A high prevalence of CVD-related risk factors and morbidity was found in this Middle Eastern PsA population, in accordance with data from other geographic regions. These results emphasize the importance of clinician awareness of the increased risk for CVD-related complications in PsA patients.

Bartonella henselae Endocarditis: An Usual Presentation of an Unusual Disease.

Bartonella species are an emerging cause of culture-negative endocarditis with more cases being diagnosed now than 25 years ago when Bartonella quintana endocarditis was first described in a patient infected with human immunodeficiency virus (HIV). Despite the disease being increasingly reported, the exact epidemiological features are not clear, with prevalence rates ranging between 2% and 10% of all cases of culture-negative endocarditis. Moreover, the mortality rate is still high, presumably because of the subacute nature and relative rareness of the disease. Bartonella endocarditis occurs more often in men, and previous valvular surgery is a major risk factor. There is insufficient data to guide definitive treatment due to the paucity of literature. A previous study demonstrated that effective antibiotic therapy for Bartonella endocarditis should include an aminoglycoside prescribed for a minimum of 2 weeks. However, the treatment strategy is a matter of expert opinion. LEARNING POINTS: Bartonella endocarditis is considered one of the most common causes of culture-negative endocarditis, yet tardy diagnosis of the disease is usually made, thus carrying a high mortality rate.Awareness of the unusual presentation of Bartonella endocarditis could potentially decrease complications and mortality rates.Contact with animals, and cats in particular, is a prominent risk factor for Bartonella henselae infection. Physicians should therefore routinely enquire about such exposure when endocarditis and especially culture-negative endocarditis is suspected.Empirical therapy should be started when culture-negative endocarditis is suspected and even when Duke criteria are not met; watchful waiting for final serological tests might be harmful, as recommended by some international authors.Most organisms causing culture-negative endocarditis are not covered in the initial treatment of infective endocarditis before or without pathogen identification recommended by the European Society of Cardiology.

The fetal outcomes of pregnancies of systemic lupus erythematosus patients in northern Israel.

OBJECTIVE: To assess the fetal outcomes of pregnancies of systemic lupus erythrematosus (SLE) patients in northern Israel. METHODS: A retrospective cohort study was conducted. The association between demographic characteristics, disease-related variables and adverse pregnancy outcome was assessed. RESULTS: Data were collected regarding 59 pregnancies of 35 SLE patients; 77.1% were Jewish patients and 22.8% Arab. None of the patients suffered from a major organ flare during pregnancy. There was no difference in the frequency of the different lupus manifestations across the two ethnic groups. The mean birth week of all pregnancies followed was 31.8 weeks. An adverse pregnancy outcome had occurred in 35.6% of the pregnancies. Intrauterine growth restriction was observed in 13.5% of the pregnancies. Antiphospholipid antibodies (APLA) positivity, past major organ involvement and a younger age at conception were associated with an adverse pregnancy outcome; however, ethnicity was not associated. DISCUSSION: The pregnancy outcomes of our cohort are similar to those previously published, worse than the general population. Ethnicity did not affect the fetal outcome.

The effect of sudden clozapine discontinuation on management of schizophrenic patients: A retrospective controlled study.

BACKGROUND: The aims of our study were (1) to compare the dose of clozapine needed to achieve remission in patients who stopped their treatment (study group) versus patients who continued taking this medication (control group) and (2) to compare the clinical characteristics of remission between these 2 groups. METHOD: We retrospectively reviewed the medical records of all treatment-resistant schizophrenic and schizoaffective patients (according to DSM-IV criteria) who were treated with clozapine over a period of 9 years, from January 1995 through December 2003. The study group consisted of 43 patients and the control group of 12 patients. All patients' files from both groups were examined, and each patient's remission was scored twice--initially on discharge from the hospital and subsequently after final discharge for the study group, or at the end of the study for the control group. RESULTS: The change of clozapine dose from the first to the last remission expressed by percentage shows a significant difference between the 43% increase in clozapine dose in the study group and the 12.5% decrease in clozapine dose in the control group (p < .001). Quality of remission assessment showed deterioration in the global remission score in the study group, while the quality of remission assessment in the control group did not show any change. CONCLUSIONS: Our findings suggest that the discontinuation of clozapine treatment leads to a deterioration in the quality of remission, with a need for an increased dose of clozapine. Further prospective studies on larger samples are needed to confirm these findings.