Senescent cells in giant cell arteritis display an inflammatory phenotype participating in tissue injury via IL-6-dependent pathways.

OBJECTIVES: Age is the strongest risk factor of giant cell arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multimarker algorithm in temporal artery biopsies (TABs) of GCA patients. METHODS: 75(+) TABs from GCA patients, 22(-) TABs from polymyalgia rheumatica (PMR) patients and 10(-) TABs from non-GCA/non-PMR patients were retrospectively retrieved and analysed. Synovial tissue specimens from patients with inflammatory arthritis and aorta tissue were used as disease control samples. Senescent cells and their histological origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype by triple costaining. GCA or PMR artery culture supernatants were applied to fibroblasts, HUVECs and monocytes with or without IL-6R blocking agent to explore the induction of IL-6-associated cellular senescence. RESULTS: Senescent cells were present in GCA arteries at higher proportion compared with PMR (9.50% vs 2.66%, respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts, and macrophages while MMP-9 by senescent fibroblasts only. IL-6(+) senescent cells were associated with the extension of vascular inflammation (transmural inflammation vs adventitia limited disease: 10.02% vs 4.37%, respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6R blockade. CONCLUSIONS: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk, suggesting a potential implication in disease pathogenesis.

Idiopathic retroperitoneal fibrosis: clinical features, treatment modalities, relapse rate in Greek patients and a review of the literature.

OBJECTIVES: Retroperitoneal fibrosis (RPF) is mostly idiopathic (iRPF); however, it can be secondary to drugs, malignancies, infections, or, as recently recognised, can be part of the IgG4-related diseases. The aim of our study was i) to describe the presenting clinical/laboratory/imaging features and treatment modalities used in patients with iRPF and ii) to evaluate factors potentially associated with disease relapse. METHODS: The medical records of patients diagnosed with iRPF and followed in four tertiary medical units in Athens, Greece from 2000 to 2018 were retrospectively evaluated. RESULTS: Sixty-seven patients with iRPF were included in the study. Seventy-three per cent were males, with a mean age at diagnosis 56.0±9.2 years. Low-back pain (63%) and constitutional symptoms (57%) were the commonest presenting symptoms. Elevated acute-phase reactants (78%), anaemia (43%) and impaired renal function (41%) were the most common laboratory findings. Serum IgG4 at diagnosis was evaluated in 36/67 patients and 36% of them had elevated levels (mean 297.7±166.3mg/dL). Diagnosis was mainly based on abdominal CT and/or MRI. Clinical/laboratory/radiological presentation did not differ between patients with elevated and normal serum IgG4 levels. Steroids were used as first-line treatment in 98%. Relapse occurred in 28.6% after a mean of 43.1±31.8 months. Relapse did not associate to initial clinical/imaging findings or to any treatment used, however patients with increased serum IgG4 had a significantly higher relapse rate (75% vs. 25%, p=0.005). CONCLUSIONS: Relapse occurred in one-fifth of patients independently of the initial clinical/radiographic presentation or treatment used. iRPF patients with baseline elevated serum IgG4 levels have a higher relapse rate.

Patterns and factors associated with pneumococcal vaccination in a prospective cohort of 1,697 patients with rheumatoid arthritis.

Introduction: Patients with rheumatoid arthritis (RA) are at increased risk for serious infections. Pneumococcal vaccination is among the most important preventive measures, however, vaccine uptake is suboptimal. We explored the rate and factors associated with pneumococcal vaccination in a contemporary RA cohort. Materials and methods: Multi-center, prospective, RA cohort study in Greece. Patient and disease characteristics and influenza and pneumococcal vaccinations were documented at baseline and 3 years later. Results: One thousand six hundred and ninety-seven patients were included and 34.5% had already received at least one pneumococcal vaccine at baseline. Among 1,111 non-vaccinated patients, 40.1% received pneumococcal vaccination during follow-up, increasing the vaccine coverage to 60.8%. By multivariate analysis, positive predictors for pneumococcal vaccination included prescription of influenza vaccine (OR = 33.35, 95% CI: 18.58-59.85), history of cancer (OR = 2.35, 95% CI: 1.09-5.06), bDMARD use (OR = 1.85, 95% CI: 1.29-2.65), seropositivity (OR = 1.47, 95% CI: 1.05-2.05), and high disease activity (DAS28-ESR, OR = 1.33, 95% CI: 1.17-1.51). Male sex (OR = 0.65, 95% CI: 0.43-0.99) was a negative predictor for pneumococcal vaccination during follow-up. Discussion: Despite increasing rates of pneumococcal vaccine coverage, 40% of RA patients remain unvaccinated. Severe disease, bDMARD use, comorbidities, and more importantly flu vaccination were the most significant factors associated with pneumococcal vaccination, emphasizing the currently unmet need for cultivating a "vaccination culture" in RA patients.

Comparative Analysis and Predictors of 10-year Tumor Necrosis Factor Inhibitors Drug Survival in Patients with Spondyloarthritis: First-year Response Predicts Longterm Drug Persistence.

OBJECTIVE: To evaluate the 10-year drug survival of the first tumor necrosis factor inhibitor (TNFi) administered to patients with spondyloarthritis (SpA) overall and comparatively between SpA subsets, and to identify predictors of drug retention. METHODS: Patients with SpA in the Hellenic Registry of Biologic Therapies, a prospective multicenter observational cohort, starting their first TNFi between 2004-2014 were analyzed. Kaplan-Meier curves and Cox regression models were used. RESULTS: Overall, 404 out of 1077 patients (37.5%) discontinued treatment (followup: 4288 patient-yrs). Ten-year drug survival was 49%. In the unadjusted analyses, higher TNFi survival was observed in patients with ankylosing spondylitis (AS) compared to undifferentiated SpA and psoriatic arthritis [PsA; significant beyond the first 2.5 (p = 0.003) years and 7 years (p < 0.001), respectively], and in patients treated for isolated axial versus peripheral arthritis (p = 0.001). In all multivariable analyses, male sex was a predictor for longer TNFi survival. Use of methotrexate (MTX) was a predictor in PsA and in patients with peripheral arthritis. Absence of peripheral arthritis and use of a monoclonal antibody (as opposed to non-antibody TNFi) independently predicted longer TNFi survival in axial disease because of lower rates of inefficacy. Achievement of major responses during the first year in either axial or peripheral arthritis was the strongest predictor of longer therapy retention (HR 0.33, 95% CI 0.26-0.41 for Ankylosing Spondylitis Disease Activity Score inactive disease, and HR 0.35, 95% CI 0.24-0.50 for 28-joint Disease Activity Score remission). CONCLUSION: The longterm retention of the first TNFi administered to patients with SpA is high, especially for males with axial disease. The strongest predictor of longterm TNFi survival is a major response within the first year of treatment.

Cardiovascular magnetic resonance imaging pattern at the time of diagnosis of treatment naïve patients with connective tissue diseases.

BACKGROUND-AIM: Cardiac involvement at diagnosis of connective tissue disease (CTD) has been described by echocardiography. We hypothesized that cardio-vascular magnetic resonance (CMR) detects occult lesions at CTD diagnosis. PATIENTS-METHODS: CMR was performed early after diagnosis in 78 treatment-naïve CTDs (aged 43±11, 59F/19M) without cardiac involvement [5 Takayasu arteritis (TA), 4 Churg Strauss syndrome (CSS), 5 Wegener granulomatosis (WG), 16 systemic lupus erythematosus (SLE), 12 rheumatoid arthritis (RA), 8 mixed connective tissue diseases (MCTD), 12 ankylosing spondylitis (AS), 3 polymyalgia rheumatica (PMR), 8 systemic sclerosis (SSc) and 5 dermatomyositis (DM)]. Acute and chronic lesions were assessed by T2>2 with positive LGE and T2<2 with positive LGE, respectively. RESULTS: In 3/5 TA, 3/4 CSS, 4/5 WG, 10/16 SLE, 9/12 RA, 6/8 MCTD, 4/12 AS, 1/3 PMR, 2/8 SSc and 2/5 DM, the T2 ratio was higher compared to normal (2.78±0.25 vs 1.5±0.2, p<0.01). Myocarditis was identified in 1 TA, 1 SLE, 1 RA, 1 SSc and 2 DM patients; diffuse, subendocardial fibrosis in 1 CSS and 1 RA patient, while subendocardial myocardial infarction in 3 SLE, 1 MCTD, 1 PMR and 2 RA patients. CMR re-evaluation after 6 and 12months of rheumatic and cardiac treatment, available in 28/52 CTDs with increased T2 ratio, showed significant improvement in T2 ratio (p<0.001), non-significant change in LGE extent and normalisation of those with impaired LV function. CONCLUSIONS: Occult CMR lesions, including oedema, myocarditis, diffuse subendocardial fibrosis and myocardial infarction are not unusual in treatment naïve CTDs and may be reversed with appropriate treatment.

Innate immunity alterations in idiopathic interstitial pneumonias and rheumatoid arthritis-associated interstitial lung diseases.

BACKGROUND: This is a prospective cohort study elucidating innate immunity in idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), rheumatoid arthritis-associated usual interstitial pneumonia (RA-UIP) and RA-associated non specific interstitial pneumonia (RA-NSIP). METHODS: 23 IPF subjects, 9 COP subjects, 5 RA-UIP subjects, 8 RA-NSIP subjects were enrolled. 10 subjects were excluded. 19 healthy subjects served as controls. Blood and bronchoalveolar lavage (BAL) were obtained. Natural killer (NK) and NKT cells, NK cells apoptosis and the expression of triggering receptor expressed on myeloid cells type 1 (TREM-1) were assessed. Tumor necrosis factor-α (TNF-α) production was measured in cell cultures after stimulation with lipopolysaccharide endotoxin (LPS) and Pam3CysSK3, and in BAL. Surface expression of Toll-like receptors (TLR) 2 and 4 on peripheral blood monocytes (PBMC's) and circulating NK cells was also assessed. RESULTS: RA-NSIP had low blood NKs, marginally insignificant (p=0.07). These NKs poorly produced TNF-α after LPS stimulation. TLR's expression on NK cells was similar throughout disease groups and controls. PBMC's mainly from IPF patients exhibited low TNF-α production after LPS stimulation but not after Pam3CysSK3 stimulation, while TLR4 expression on PBMC's was found normal in all study groups. TLR2 expression on PBMC's was increased in IPF, but mainly in COP, RA-UIP and RA-NSIP (p=0.015). TREM-1 expression was significant on COP monocytes and on COP neutrophils versus controls. RA-NSIP monocytes also exhibited TREM-1 expression (p=0.07). Decreased TNF-α concentration in BAL was finally observed in IPF and RA-UIP. CONCLUSIONS: Innate immunity in the lungs and the peripheral circulation in IPF and RA-UIP are similar and more fibrotic than in RA-NSIP which is characterized by NK cell depletion and dysfunction. TREM-1 and TLR's likely affect patterns of inflammation in various interstitial lung diseases.

Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival.

OBJECTIVE: To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients. METHODS: This study is a prospective cohort study of 1208 active RA patients. Effectiveness, drug survival, and serious adverse events during entire follow-up (median 2.9 years) were monitored. RESULTS: EULAR and CDAI responses were comparable between the three agents (EULAR good/moderate responses at 12 months ranged 76-79%). At 12 months, 15-23% achieved remission. For adalimumab and etanercept, adjusted hazard rate (HR) for EULAR/ACR remission (reference: infliximab) was 2.7 and 2.1 (95% confidence interval was 1.7-4.1 and 1.3-3.4, respectively); males (HR 1.6; 1.1-2.4), use of glucocorticoids (HR 2.0; 1.3-3.0), and swollen joint count >7 (HR 0.36; 0.24-0.55) were independent predictors. Five-year drug survival was 31%, 43%, and 49% for infliximab, adalimumab, and etanercept, respectively (p = 0.010). Infliximab was associated with significantly more withdrawals due to adverse events. Disease activity, CRP, and use of glucocorticoids predicted efficacy-related drug survival; age, use of methotrexate, and prior DMARDs failures predicted safety-related survival. Risk for serious infections was lower with adalimumab (odds ratio [OR] 0.62; 0.38-1.00) or etanercept (OR 0.39; 0.21-0.72) than infliximab, independent of the effects of age (OR 1.65; 1.37-2.00 per 10 years), tender joint count >10 (OR 1.86; 1.21-2.86), and glucocorticoids >35mg/week (OR 1.83; 1.12-2.99). CONCLUSIONS: Response rates were comparable among anti-TNF agents. Overall, 5-year drug survival was below 50%, with infliximab demonstrating increased safety-related discontinuations. Remission rates are low in clinical practice. Strategies to increase effectiveness and long-term survival of anti-TNF agents in RA are needed.

Adalimumab is effective and well tolerated in treating patients with ankylosing spondylitis who have advanced spinal fusion.

OBJECTIVES: To evaluate the effectiveness and safety of adalimumab in treating patients with AS and advanced structural damage. METHODS: Patients with active AS [Bath AS Disease Activity Index (BASDAI) > or =4] received 40 mg of adalimumab every other week plus their standard anti-rheumatic therapies in this 12-week, open-label study. Investigators documented the presence or absence of advanced ankylosis based on previous radiographs. Stages IV (from 50 to <80% involvement in more than two spinal segments) and V (> or =80% spinal involvement, including bamboo spine) disease were considered as advanced AS. Effectiveness parameters included Assessment of SpondyloArthritis international Society (ASAS) criteria, BASDAI response and achievement of optimal sleep. Adverse events were reported throughout therapy and at a 70-day follow-up. RESULTS: The analysis population included 897 patients whose AS was not advanced (i.e. Stages I-III), 31 with Stage IV disease and 41 with Stage V disease. At Week 12, ASAS40/BASDAI 50 responses were achieved by 54%/57% of patients with AS Stages I-III, 48%/58% with AS Stage IV and 54%/66% with AS Stage V, respectively. ASAS partial remission rates were 30, 26 and 7% for patients with Stages I-III, IV and V disease, respectively. Serious infections occurred in three (<1%) patients with AS Stages I-III and in one (1%) patient with AS Stage V. CONCLUSIONS: After 12 weeks of adalimumab therapy, patients with advanced but active AS, including those with structural damage of > or =80% of the vertebrae, achieved improvements in signs and symptoms similar to those attained by patients whose AS was not advanced.