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.

Glucocorticoid discontinuation rate and risk factors for relapses in a contemporary cohort of patients with giant cell arteritis.

The rates of relapses and therapy discontinuation in patients with giant cell arteritis (GCA) in the modern therapeutic era have not been defined. We aimed to evaluate the glucocorticoid (GC) discontinuation rate and the factors associated with relapses in a contemporary GCA cohort. Patient and treatment data were collected cross-sectionally at first evaluation and 2 years later (second evaluation), in a multicenter, prospective GCA cohort. Predictors of relapses were identified by logistic regression analyses. 243 patients with GCA were initially included (67% women, mean age at diagnosis: 72.1 years, median disease duration: 2 years) while 2 years later complete data for 160 patients were available and analyzed. All patients had received GCs at diagnosis (mean daily prednisolone dose: 40 mg) while during follow-up, 37% received non-biologic and 16% biologic agents, respectively. At second evaluation, 72% of patients were still on therapy (GCs: 58% and/or GC-sparing agents: 29%). Relapses occurred in 27% of patients during follow-up; by multivariable logistic regression analysis, large vessel involvement at diagnosis [odds ratio (OR) = 4.22], a cardiovascular event during follow-up (OR = 4.60) and a higher initial GC daily dose (OR = 1.04), were associated with these relapses. In this large, real-life, contemporary GCA cohort, the rates of GC discontinuation and relapses were 40% and 27%, respectively. Large vessel involvement, a higher GC dose at diagnosis and new cardiovascular events during follow-up were associated with relapses.

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.

Remission or low disease activity at pregnancy onset are linked to improved foetal outcomes in women with systemic lupus erythematosus: results from a prospective observational study.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients show variably increased risk for pregnancy complications. We analysed pregnancy outcomes (foetal and maternal), patterns of disease activity and use of medications in a contemporary Caucasian SLE population. METHODS: Prospective observational study, involving hospital units and private rheumatologists in Greece, of incident pregnancies (period 2015-2018) in women with SLE. Clinical and obstetrical monitoring was performed at regular intervals up to 9 months post-partum. Regression and mixed model analyses were used to determine predictors for adverse foetal outcomes and flares. RESULTS: We monitored 82 pregnancies in 64 SLE patients. Foetal loss, prematurity and small for gestational age neonate occurred at 15.8%, 34.1% and 8.5%, respectively; 53.7% of pregnancies were complicated with at least one adverse outcome. Patients with antiphospholipid antibodies (aPL) had increased risk (odds ratio [OR] 5.67, p=0.015), whereas those at low disease activity at pregnancy onset were protected (OR 0.20, p=0.024) against foetal complications. Persistent activity and glucocorticoid intake during pregnancy also predicted poor foetal outcomes. SLE patients experienced an average 1.08 mild/moderate and 0.27 severe flares. The latter occurred more frequently post-partum, in patients with alopecia (OR 8.92, p=0.003), hypocomplementaemia (OR 10.34, p=0.038) and nephritis (OR 7.32, p=0.052). Lupusactivity post-labour was paralleled by decreased use of hydroxychloroquine, glucocorticoids and azathioprine. CONCLUSIONS: In SLE women, foetal complications are common especially in the presence of aPL and increased activity, which corroborates the importance of pregnancy planning and tight disease control at pregnancy onset. Flares, mostly mild or moderate, can occur both during and after pregnancy.

COVID-19 infection among autoimmune rheumatic disease patients: Data from an observational study and literature review.

The impact of SARS-CoV-2 infection in patients with autoimmune/auto-inflammatory rheumatic diseases (AARD) under immunomodulatory treatment has been a focus of interest during the COVID-19 pandemic. In this observational study, demographic data, disease related features and comorbidities, COVID-19 manifestations and outcome as well as antibody responses to SARS-CoV-2 were recorded among 77 consecutive patients with underlying AARD infected by SARS-CoV-2. Analysis of data was performed using univariate and multivariate models. Most patients (68.8%) had a mild COVID-19 course. The predominant clinical manifestations were fatigue (58.4%), low grade fever (45.4%) and upper respiratory tract symptoms (68.8%). About a quarter of patients required hospitalization (23.3%) and the mortality rate was 1.3%. Regarding COVID-19 severity, prior treatment with corticosteroids, mycophenolate mofetil or rituximab was more common in patients who developed a more serious disease course (60.0 vs 29.9%, p = 0.003, 40.0 vs 7.5%, p = 0.003, 10.0 vs 0.0%, p = 0.009, respectively). When disease related features and comorbidities were considered in multivariate models, older age and lung disease in the context of the AARD were found to be independent predictive factors for hospitalization (OR [95%]: 1.09 [1.03-1.15] and 6.43 [1.11-37.19]). Among COVID-19 related features, patients with shortness of breath and high-grade fever were more likely to get hospitalized (OR [95%]: 7.06 [1.36-36.57], 12.04 [2.96-48.86]), while anosmia was independently associated with lower hospitalization risk (OR [95%]: 0.09 [0.01-0.99]). Though the majority of AARD patients displayed a mild COVID-19 course, certain underlying disease features and COVID-19 related manifestations should prompt alertness for the physician to identify patients with AARD at high risk for severe COVID-19 and need for hospitalization.

Comparable or higher prevalence of comorbidities in antiphospholipid syndrome vs rheumatoid arthritis: a multicenter, case-control study.

OBJECTIVES: Evidence on comorbidity prevalence in antiphospholipid syndrome (APS) and its difference from high comorbidity burden rheumatic diseases is limited. Herein, we compare multiple comorbidities between APS and RA. METHODS: A total of 326 patients from the Greek APS registry [237 women, mean age 48.7 (13.4) years, 161 primary APS (PAPS), 165 SLE-APS] were age/sex matched (1:2 ratio) with 652 patients from a Greek multicentre RA cohort of 3115 patients. Prevalence of cardiovascular (CV) risk factors, stroke, coronary artery disease (CAD), osteoporosis, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), depression and neoplasms were compared between APS and RA patients using multivariate regression analysis. RESULTS: Ηyperlipidemia and obesity (ΒΜΙ ≥ 30 kg/m2) were comparable while hypertension, smoking, stroke and CAD were more prevalent in APS compared with RA patients. Osteoporosis and depression were more frequent in APS, while DM, COPD and neoplasms did not differ between the two groups. Comparison of APS subgroups to 1:2 matched RA patients revealed that smoking and stroke were more prevalent in both PAPS and SLE-APS vs RA. Hypertension, CAD and osteoporosis were more frequent only in SLE-APS vs RA, whereas DM was less prevalent in PAPS vs RA. Hyperlipidaemia was independently associated with CV events (combined stroke and CAD) in PAPS and SLE-APS, while CS duration was associated with osteoporosis in SLE-APS. CONCLUSION: Comorbidity burden in APS (PAPS and SLE-APS) is comparable or higher than that in RA, entailing a high level of diligence for CV risk prevention, awareness for depression and CS exposure minimization.

Incidence, risk factors and validation of the RABBIT score for serious infections in a cohort of 1557 patients with rheumatoid arthritis.

OBJECTIVES: Predicting serious infections (SI) in patients with rheumatoid arthritis (RA) is crucial for the implementation of appropriate preventive measures. Here we aimed to identify risk factors for SI and to validate the RA Observation of Biologic Therapy (RABBIT) risk score in real-life settings. METHODS: A multi-centre, prospective, RA cohort study in Greece. Demographics, disease characteristics, treatments and comorbidities were documented at first evaluation and one year later. The incidence of SI was recorded and compared with the expected SI rate using the RABBIT risk score. RESULTS: A total of 1557 RA patients were included. During follow-up, 38 SI were recorded [incidence rate ratio (IRR): 2.3/100 patient-years]. Patients who developed SI had longer disease duration, higher HAQ at first evaluation and were more likely to have a history of previous SI, chronic lung disease, cardiovascular disease and chronic kidney disease. By multivariate analysis, longer disease duration (IRR: 1.05; 95% CI: 1.005, 1.1), history of previous SI (IRR: 4.15; 95% CI: 1.7, 10.1), diabetes (IRR: 2.55; 95% CI: 1.06, 6.14), chronic lung disease (IRR: 3.14; 95% CI: 1.35, 7.27) and daily prednisolone dose ≥10 mg (IRR: 4.77; 95% CI: 1.47, 15.5) were independent risk factors for SI. Using the RABBIT risk score in 1359 patients, the expected SI incidence rate was 1.71/100 patient-years, not different from the observed (1.91/100 patient-years; P = 0.97). CONCLUSION: In this large real-life, prospective study of RA patients, the incidence of SI was 2.3/100 patient-years. Longer disease duration, history of previous SI, comorbidities and high glucocorticoid dose were independently associated with SI. The RABBIT score accurately predicted SI in our cohort.

Combined brain and heart magnetic resonance imaging in systemic vasculitides: fiction or real need?

Systemic vasculitides (SVs) is a group of diseases characterised by inflammation/necrosis of the blood vessel wall in various organs. Simultaneous brain and heart involvement is a cause of increased morbidity/mortality in SV. We aimed to present evidence of concurrent brain/heart involvement in SV and the role of a combined brain/heart magnetic resonance imaging (MRI) in their risk stratification. Cerebral vasculitis (CV) can be presented as focal deficits, seizures, headache, neuropsychiatric manifestations or cognitive dysfunction and cardiovascular disease (CVD) as myocardial/vascular inflammation, perfusion/function defects and fibrosis. MRI is a non-invasive, non-radiating technique that allows the reliable identification of intraparenchymal brain lesions and the detection of myocardial/vascular inflammation and fibrosis. However, its use in SV is currently hampered by high cost, lack of availability/expertise and lack of awareness among the clinicians. Although there are no clinical data supporting the combined use of brain/heart MRI in asymptomatic SV, it would be called for in cases with clinical suspicion of brain/heart involvement, especially in those at high risk for CVD/stroke such as SLE/APS. Furthermore, it may be of value in SV with multi-organ involvement, cognitive dysfunction or other neuropsychiatric symptoms with concurrent cardiac involvement, presenting as typical or atypical symptoms with normal routine cardiac evaluation, new onset of arrhythmia and/or HF.

Safety profile of repeated rituximab cycles in unselected rheumatoid arthritis patients: a long-term, prospective real-life study.

OBJECTIVES: To evaluate the long-term safety of rituximab (RTX) in rheumatoid arthritis (RA) patients in daily clinical practice. METHODS: This was a multicentre (17 Greek Rheumatology sites), prospective, long-term, pharmacovigilance study of patients with moderate to severe RA and an inadequate response or intolerance to ≥1 anti-tumour necrosis factor (TNF) agents. Adverse events (AEs) were recorded and collected prospectively every 2-6 months. RESULTS: 234 patients (mean age: 59±12.5, 79.5% women, mean DAS28: 5.35±1.32) were included and followed for 27.7 months (median). The overall AEs, serious AE (SAEs) and serious infection (SIEs) rate were 48.36, 6.68 and 2.53/100 patient-years, respectively. Three cases of hepatitis B virus (HBV) reactivation were recorded (two in chronic and one in past HBV infection). Withdrawals due to AEs (5.6%) occurred more frequently during the first cycles of RTX therapy while repeated RTX cycles were not associated with an increased risk of AEs. There were 3 deaths with an incidence rate of 0.69/100 patient-years. Age ≥65 years was associated with a higher incidence rate ratio of AEs and SAEs as compared to <65 years (1.53, p=0.002 and 2.88, p=0.005, respectively). Drug retention rate during 434.28 patient-years of follow-up was 57.3%. Factors associated with drug discontinuation by multivariate analysis included age, baseline swollen joint count and no use of concomitant methotrexate therapy. CONCLUSIONS: Long-term RTX therapy in a real-life RA cohort, did not reveal any new safety issues. Advanced age was associated with increased risk of AEs and premature drug discontinuation.

Treatment with the first TNF inhibitor in rheumatoid arthritis patients in the Hellenic Registry of Biologic Therapies improves quality of life especially in young patients with better baseline functional status.

OBJECTIVES: To assess in daily practice in patients with rheumatoid arthritis (RA) the effect of treatment with first tumour necrosis factor-α inhibitor (TNFi) in quality of life (Qol), disease activity and depict possible baseline predictors for gains in Qol. METHODS: Patients followed prospectively by the Hellenic Registry of Biologic Therapies were analysed. Demographics were recorded at baseline, while RA-related characteristics at baseline and every 6 months. Paired t-tests were used to detect divergences between patient-reported (Health Assessment Questionnaire (HAQ), EuroQol (EQ-5D)) and clinical tools (Disease Activity Score-28 joints (DAS28)). Clinical versus self-reported outcomes were examined via cross-tabulation analysis. Multiple regression analysis was performed for identifying baseline predictors of improvements in QALYs. RESULTS: We analysed 255 patients (age (mean±SD) 57.1±13.0, disease duration 9.2±9.1 years, prior non-biologic disease-modifying anti-rheumatic drugs 2.3±1.2). Baseline EQ-5D, HAQ and DAS28 were 0.36 (0.28), 1.01 (0.72) and 5.9 (1.3), respectively, and were all significantly improved after 12 months (0.77 (0.35), 0.50 (0.66), 3.9 (1.5), respectively, p<0.05 for all). 90% of patients who improved from high to a lower DAS28 status (low-remission or moderate) had clinically important improvement in Qol (phi-coefficient=0.531,p<0.05). Independent predictors of gains in Qol were lower baseline HAQ, VAS global and younger age (adjusted R2=0.27). CONCLUSIONS: In daily practice TNFi improve both disease activity and Qol for the first 12 months of therapy. 90% of patients who improved from high to a lower DAS28 status had clinically important improvement in Qol. Younger patients starting with lower HAQ and VAS global are more likely to benefit.

The Role of Myositis-Specific and Myositis-Associated Autoantibodies and the Activation of Type I Interferon Pathway in the Generation of Clinical Phenotypes of Inflammatory Myopathies.

Idiopathic inflammatory myopathies (IIMs) are a group of heterogeneous autoimmune diseases with a prevalence of 20 cases per 100000 of population. Despite their diversity, IMMs are characterised by several common clinical features such as muscle inflammation, proximal muscle weakness, abnormal electromyography and/or muscle biopsy. Over the last years, it has been increasingly recognised that an array of autoantibodies known as myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs) are associated with distinct clinical phenotypes and diverse prognosis. Although the exact underlying mechanism of IIMs is not fully understood, accumulating data suggest that the activation of type I interferon pathway plays a central role in disease development. Previous studies have reported the upregulation of type I interferon (IFN) induced genes in peripheral blood and muscle biopsies derived from myositis patients. Given the heterogeneity of inflammatory myopathies along with the central role of type I IFN pathway in disease pathogenesis, the aim of the current study is to elucidate the link between distinct clinical phenotypes of inflammatory myopathies with the presence of serum MSAs or MAAs, as well as with type I IFN activation.

Real-Life Outcome of Lupus Nephritis with Current Therapies: Study Protocol of a Multicentre Observational Study.

Lupus nephritis (LN) affects a significant proportion of patients with systemic lupus erythematosus (SLE) and is characterised by increased morbidity and mortality. The updated joint EULAR/European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) recommendations for the management of LN have set as target of therapy the optimisation (preservation or improvement) of kidney function, accompanied by a reduction in proteinuria of at least 25% by 3 months, 50% by 6 months, and below 500-700 mg/g by 12 months (complete clinical response). It is currently unknown what proportion of Greek patients with LN reach these proposed targets with the current available treatments. At the same time, recent successful phase 3 trials have led to the approval of both belimumab and voclosporin for the treatment of patients with LN and have steered discussions as to whether the "induction-maintenance" paradigm should be substituted by an early combination treatment for all patients. To inform future therapeutic decisions and facilitate the positioning of these new drugs in the therapeutic algorithm of LN, the current study protocol aims to map the unmet needs in the treatment of LN in Greece, by quantifying the proportion of patients who attain the recommended treatment targets in everyday clinical practice.

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.

Intravenous immunoglobulin treatment for pregnancy-associated dermatomyositis.

Pregnancy-associated dermatomyositis (DM) is a rare disorder, until recently treated only with corticosteroids due to the toxicity of other immunosuppressive agents for the fetus. We present a pregnant woman with DM treated successfully with intravenous immunoglobulin (IVIG) and medium dose corticosteroids. A 42-year-old woman presented with a rash, muscle weakness and increased muscle enzymes on the 15th week of her first pregnancy. After the diagnosis of DM she was treated with the combination of medium dose corticosteroids and IVIG. The patients' symptoms resolved rapidly. No complications were noted for either her or the fetus. Both she and her son remain disease-free after 6 years follow-up. In conclusion, IVIG treatment is a safe and effective alternative for pregnancy-associated DM.

Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3): A Novel Marker for Lymphoma Development among Patients with Young Onset Sjogren's Syndrome.

BACKGROUND: Primary Sjogren's syndrome (SS) is an autoimmune disease with a strong predilection for lymphoma development, with earlier disease onset being postulated as an independent risk factor for this complication. Variations of the Leukocyte immunoglobulin-like receptor A3(LILRA3) gene have been previously shown to increase susceptibility for both SS and non-Hodgkin B-cell lymphoma (B-NHL) in the general population. We aimed to investigate whether variations of the LILRA3 gene could predispose for lymphoma development in the context of SS. METHODS: Study population, all of Greek origin, included 101 SS cases with a current or previous diagnosis of lymphoma (SS-lymphoma, SS-L) and 301 primary SS patients not complicated by lymphoma (SS-non-lymphoma, SS-nL). All SS patients fulfilled the 2016 SS American College of Rheumatology/European league against Rheumatism (ACR/EULAR) classification criteria. A total of 381 healthy controls (HC) of similar age/sex/race distribution were also included. On the basis of the age of SS onset and the presence or absence of adverse predictors for lymphoma development, SS patients were further stratified into younger (≤40 years) and older (>40 years) age of disease onset, as well as into high/medium and low risk groups. Polymerase chain reaction (PCR) was implemented for the detection of the following LILRA3 gene variants: homozygous non-deleted or functional wild type (+/+) heterozygous (+/-) and homozygous deleted (-/-). LILRA3 serum protein levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 85 individuals (29 SS-L, 35 SS-nL patients and 21 HC). RESULTS: While no statistically significant differences were detected in the overall frequency of LILRA3 gene variants between SS-L, SS-nL and HC groups, LILRA3 serum protein levels were increased in the SS-L group compared to HC (1.27 ± 1.34 vs. 0.38 ± 0.34 ng/mL, p-value: 0.004). After stratification according to the age of SS onset and history of lymphoma, as well as the presence or absence of adverse predictors for lymphoma development, the prevalence of the functional LILRA3 gene variant was found to be significantly increased in the young onset SS-L group compared to the HC of similar age and sex distribution (100% vs. 82.9%, p = 0.03), as well as in the high/medium risk SS compared to the low risk SS (91.3 vs. 78.3%, p = 0.0012). Of note, young onset SS-L and SS-nL groups displayed higher LILRA3 serum levels compared to their older counterparts (p-values: 0.007 and 0.0005, respectively). CONCLUSION: The functional LILRA3 gene variant increases susceptibility to SS-related lymphoma development in patients with a disease onset of <40 years old, implying that genetically determined deranged immune responses in younger SS individuals could underly their pronounced risk for lymphoma development.

Serious infections in ANCA-associated vasculitides in the biologic era: real-life data from a multicenter cohort of 162 patients.

BACKGROUND: Serious infections (SI) are common in patients with ANCA-associated vasculitides (AAV) like granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Real-life data regarding their incidence and predisposing factors-after the introduction of B cell depleting agents-are limited while data quantifying the risk per treatment modality and year of the disease are missing. Here, we aim to describe in details the incidence and the risk factors for SI in a contemporary AAV cohort. METHODS: Multicenter, observational, retrospective study of AAV patients followed in three tertiary referral centers. RESULTS: We included 162 patients with GPA (63%) and MPA (37%), males 51.9%, mean age 60.9 years, ΑΝCA+ 86%, and generalized disease 80%. During follow-up (891.2 patient-years, mean 5.4 years), 67 SI were recorded in 50 patients at an incidence rate of 7.5 per 100 patient-years. The SI incidence rate was higher during induction with cyclophosphamide (CYC) compared to rituximab (RTX, 19.3 vs. 11.3 per 100 patient-years, respectively) while it was lower and comparable between RTX and other regimens (5.52 vs. 4.54 per 100 patient-years, respectively) in the maintenance phase. By multivariate analysis, plasmapheresis (PLEX) and/or dialysis was a strong predictor for an SI during the 1st year after diagnosis (OR = 3.16, 95% CI 1.001-9.96) and throughout the follow-up period (OR = 5.21, 95% CI 1.93-14.07). In contrast, a higher baseline BVAS (OR = 1.11, 95% CI 1.01-1.21) was associated with SI only during the 1st year. CONCLUSIONS: In this real-life study of patients with AAV, the SI incidence was higher during CYC compared to RTX induction while there was no difference between RTX and other agents used for maintenance therapy. Higher disease activity at baseline and need for PLEX and/or dialysis were independent factors associated with an SI.

Development of an ANCA-Associated Vasculitides Patient Registry in Greece.

Despite the recent advances in treatment, antineutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) are among the rheumatic diseases with the highest morbidity and mortality. These outcomes are affected by a variety of factors apart from the disease itself, and are driven by infections, cardiovascular disease and drug toxicity. Even after the induction of remission, patients and their treating physicians are challenged by frequent relapses, accrual of chronic damage and impaired quality of life. Given their rarity along with their heterogeneous disease spectrum, patient registries are of utmost need for the study of all aspects of AAV. Already established AAV registries have a significant contribution in the apprehension of these diseases outside the strict context of clinical trials, and are becoming increasingly important as new drugs and treatment strategies are about to be introduced in daily practice. We here describe the design of a contemporary, web-based and easy-to-use patient registry specifically for patients with AAV, including all the necessary domains suggested by international working groups. This project is anticipated to contribute in better understanding of AAV in our country, with a future prospect of contributing to and sharing data with other international registries.

The Role of Novel Autoantibodies in the Diagnostic Approach and Prognosis of Patients with Raynaud's Phenomenon.

Raynaud's phenomenon (RP) is a condition characterised by distinct colour changes of the digits upon exposure to sympathomimetic conditions, such as cold temperature. It can be either primary or secondary, depending on whether it presents alone or as part of an underlying disorder. One of the most common causes of secondary RP are systemic autoimmune rheumatic diseases (SARDs), in which RP may precede the onset of other autoimmune features by many years. Thus, timely and accurate recognition of secondary RP is of great importance as it alters patient management and prognosis. An important step in the diagnostic approach of RP is the detection of antinuclear antibodies (ANAs) by indirect immunofluorescence. However, identification of specific autoantibodies is not yet common practice, though many of them have shown important clinical associations. Moreover, the role of some autoantibodies has not yet been elucidated, given their relatively recent discovery and low reported prevalence rates in autoimmune population. The goal of this study is to reveal clinical associations of these novel autoantibodies in SARDs through the application of an extended serology workup in patients presenting with RP.

Rheumatoid arthritis patients on persistent moderate disease activity on biologics have adverse 5-year outcome compared to persistent low-remission status and represent a heterogeneous group.

BACKGROUND: The long-term outcome of rheumatoid arthritis (RA) patients who in clinical practice exhibit persistent moderate disease activity (pMDA) despite treatment with biologics has not been adequately studied. Herein, we analyzed the 5-year outcome of the pMDA group and assessed for within-group heterogeneity. METHODS: We included longitudinally monitored RA patients from the Hellenic Registry of Biologic Therapies with persistent (cumulative time ≥ 50% of a 5-year period) moderate (pMDA, 3.2 < DAS28 ≤ 5.1) or remission/low (pRLDA, DAS28 ≤ 3.2) disease activity. The former was further classified into persistent lower-moderate (plMDA, DAS28 < 4.2) and higher-moderate (phMDA, DAS28 ≥ 4.2) subgroups. Five-year trajectories of functionality (HAQ) were the primary outcome in comparing pRLDA versus pMDA and assessing heterogeneity within the pMDA subgroups through multivariable mixed-effect regression. We further compared serious adverse events (SAEs) occurrence between the two groups. RESULTS: We identified 295 patients with pMDA and 90 patients with pRLDA, the former group comprising of plMDA (n = 133, 45%) and phMDA (n = 162, 55%). pMDA was associated with worse 5-year functionality trajectory than pRLDA (+ 0.27 HAQ units, CI 95% + 0.22 to + 0.33; p < 0.0001), while the phMDA subgroup had worse 5-year functionality than plMDA (+ 0.26 HAQ units, CI 95% 0.18 to 0.36; p < 0.0001). Importantly, higher persistent disease activity was associated with more SAEs [pRLDA: 0.2 ± 0.48 vs pMDA: 0.5 ± 0.96, p = 0.006; plMDA: 0.32 ± 0.6 vs phMDA: 0.64 ± 1.16, p = 0.038]. Male gender (p = 0.017), lower baseline DAS28 (p < 0.001), HAQ improvement > 0.22 (p = 0.029), and lower average DAS28 during the first trimester since treatment initiation (p = 0.001) independently predicted grouping into pRLDA. CONCLUSIONS: In clinical practice, RA patients with pMDA while on bDMARDs have adverse long-term outcomes compared to lower disease activity status, while heterogeneity exists within the pMDA group in terms of 5-year functionality and SAEs. Targeted studies to better characterize pMDA subgroups are needed, in order to assist clinicians in tailoring treatments.

Development and Implementation of a Pilot Registry for Monitoring the Efficacy and Safety of Novel Therapies in Patients with Systemic Lupus Erythematosus.

The therapeutic armamentarium in Systemic Lupus Erythematosus (SLE) is expanding with the introduction of novel biologic and small-molecule agents. Complementary to randomized controlled trials, registry-based studies are advantageous due to the inclusion of a wider range of patients from daily practice and the potential for long-term monitoring of the efficacy and safety of therapies. Moreover, data from registries can be used to identify disease phenotypes that best respond to biologic agents, and to correlate clinical response with parameters such as co-administered therapies and comorbidities. In this project, we will use the configuration of the Hellenic Registry of Biologic Therapies for inflammatory arthritides in order to design a dedicated SLE module with variables pertaining to global and organ-specific disease activity, severity, flares, organ damage/outcome, comorbidities and adverse events. The second stage will involve the pilot implementation of this platform for the multicentric registration of SLE patients who are treated with belimumab. The significance lies in the development of a structured registry that enables the assessment of the disease burden and the long-term efficacy and safety of existing and future biological agents in SLE. Piloting the registry can serve as a basis for establishing nationwide collaborative efforts.