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 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.

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.

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.

Immune-Mediated Disease Flares or New-Onset Disease in 27 Subjects Following mRNA/DNA SARS-CoV-2 Vaccination.

BACKGROUND: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. METHODS: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. FINDINGS: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. INTERPRETATION: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. FUNDING: none.

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.

High Dimensional Analyses of Circulating Immune Cells in Psoriatic Arthritis Detects Elevated Phosphorylated STAT3.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, affecting up to 40% of patients with psoriasis. Constitutive expression by CD4+ T cells of an active form of STAT3, a signal transducer and transcription factor, has been shown to induce many of the major features of PsA in an animal model. We used high dimensional mass cytometry (CyTOF) to probe ex-vivo levels of phosphorylated STAT3 (pSTAT3) in circulating immune cell subpopulations from PsA patients during active and inactive states. We evaluated the frequency of 16 immune cell populations and the levels of the activated forms of STAT3 (pSTAT3) and, for comparison, STAT1 (pSTAT1) and Src (pSrc) in whole blood fixed shortly after collection. In addition to PsA patients, we studied active rheumatoid arthritis (RA) patients. Increased levels of pSTAT3 were found in all the CD4+ T cell subsets analyzed, specifically, Th1, Th2, Th17, T follicular helper (Tfh) and T regulatory (Treg) as well as in CD14+CD16- (classical) monocytes from active PsA patients compared to inactive patients. After correcting for body mass index (BMI), smoking and conventional disease modifying antirheumatic drugs (c-DMARDs), levels of pSTAT3 levels remained increased in Th1 and Tfh CD4+ T cells, and in CD14+CD16- monocytes from active patients compared to inactive patients. No differences between the patient groups were observed for pSTAT1 or pSrc. No differences were found between the active PsA and active RA groups after correction for multiple testing. During active PsA, circulating Th1 and Tfh CD4+ T cells, and CD14+CD16- monocytes expressing high levels of pSTAT3 may play a role in PsA pathophysiology, perhaps by migration to inflamed sites.

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.

Immunogenicity and safety of vaccination against seasonal influenza vaccine in patients with psoriatic arthritis treated with secukinumab.

OBJECTIVE: To assess the immunogenicity and safety of vaccination against seasonal influenza in psoriatic arthritis (PsA) patients treated with secukinumab versus healthy controls (HC). METHODS: PsA patients administered secukinumab for ≥3 months and HC received the Sanofi Pasteur vaccine composed of 3 antigens (H3N3, H1N1, and B) and underwent clinical and laboratory assessments on the day of vaccination and 4-6 weeks later. Immunogenicity of the vaccine was evaluated by hemagglutination inhibition assay against those 3 antigens. Responders to each antigen were defined by a 4-fold increase in the antigen titer or by seroconversion in patients whose baseline level was <1/40. RESULTS: Thirty-two consecutive PsA patients treated with secukinumab for ≥3 months comprised the study group, 10 of whom received concomitant conventional synthetic disease-modifying drugs, mostly methotrexate. There were 17 age- and gender-matched HC (median age 48.5 years, 6 females). The geometric mean titers of each antigen increased significantly in both groups. The number of responders in each group was similar for H3N2 and H1N1, and significantly higher for B/Brisbane in the PsA group. The proportion of patients with a seroprotective level (a titer >1/40) was high and similar in both groups. There was no correlation between the response rate and age, gender, or selected parameters of disease activity (tender/swollen joint counts, Leeds enthesitis index, physician and patient global assessment, psoriasis area severity index, and C-reactive protein). No disease exacerbation was observed following the vaccination. No serious adverse effects were observed in both groups during the study period. CONCLUSION: Secukinumab treatment does not affect the humoral response to influenza vaccine of patients with PsA.

Increased Prevalence of Metabolic Syndrome and Adipocytokine Levels in a Psoriatic Arthritis Cohort.

OBJECTIVE: The aims of this study were to evaluate the prevalence of metabolic syndrome (MetS) in psoriatic arthritis (PsA) patients according to the most recent definition in a Mediterranean population and to determine its association with biomarkers of inflammation and serum adipocytokine levels. METHODS: Demographic, clinical, and laboratory data were collected on 74 patients with PsA and 82 control subjects. The presence of MetS was determined according to the current "harmonization" definition. Serum adipocytokines were analyzed. Continuous variables were compared by t test and discrete variables by χ test. Multivariate regression models compared the association between the presence of MetS and the blood levels of adipocytokines. RESULTS: The prevalence of MetS was higher in PsA patients compared with the control group: 54.8% versus 36.6%, respectively (P = 0.02; odds ratio, 2.33; 95% confidence interval, 1.16-4.69). The main difference between the 2 groups was waist circumference. No association was found between MetS and parameters of articular and skin disease activity or treatment. Leptin levels and leptin/adiponectin ratio were higher in PsA patients compared with control subjects: 83.4 versus 51.7 ng/mL (P = 0.001) and 6.3 × 10 versus 4.1 × 10 (P = 0.015), respectively. There was no significant difference in the adiponectin levels between the groups. CONCLUSIONS: The prevalence of MetS was higher in PsA patients compared with non-PsA control subjects in this Mediterranean population. Clinicians caring for PsA patients ought to be aware of the increased risk of MetS in PsA patients, confirmed in different regions worldwide. The increased MetS seems to be linked to central obesity in these patients, and appropriate treatment recommendations are advised.

Clinical and demographic characteristics of patients with psoriatic arthritis in northern Israel.

Disease patterns and manifestations may vary among different populations and change over time. The purpose of our study was to define the demographic, clinical, roentgenologic, and laboratory findings in a recent cohort of psoriatic arthritis patients followed up in rheumatology clinics in northern Israel. We conducted a cross-sectional study of 149 psoriatic arthritis patients. Demographic, clinical, laboratory, and radiological data, with emphasis on the pattern of arthritis, treatment regimens, and co-morbidities were obtained from patient interviews and rheumatology file reviews. The mean age of our patients was 58.2, with a female preponderance (57.3%). Skin involvement preceded the arthritis or was diagnosed simultaneously in 90.1% of cases. The most common joint involvement was an RA-like arthritis (49.7% of the patients) correlating positively with age, female gender, and disease duration. Dactylitis and nail involvement were observed in 33.6 and 36.2% of the patients, respectively. Radiographic bone erosions were noted in a third of the patients, correlating with DIP and RA-like arthritis patterns. Most patients were treated with methotrexate (73.8%) and a combination therapy (41.4%). An increased incidence of hypertension, hyperlipidemia, and diabetes mellitus was noted in our cohort compared to the general Israeli population. Our survey, the first of its kind conducted in Israel, noted a relative increase in the polyarticular manifestation of PsA and a decrease in spondyloarthropathy, compared to historic series, with more aggressive disease found in women above the age of sixty. These findings are in line with recent surveys.