Autoinflammatory syndromes with coexisting variants in Mediterranean FeVer and other genes: Utility of multiple gene screening and the possible impact of gene dosage.

OBJECTIVE: To assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype. METHODS: Consecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile- and 21 with adult-onset disease. RESULTS: The candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still's disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease-causing variants in the same genes were also associated with an overall more severe SAID phenotype. CONCLUSION: Co-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.

The effects of golimumab on patient centric outcomes amongst rheumatoid arthritis patients in Greece. The GO-Q study.

This study aimed at assessing the impact of golimumab on health-related quality of life (HRQoL) and other patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) in real-world settings. GO-Q was an observational, prospective, 12-month study, which recruited patients with moderate-to-severely active RA initiating golimumab treatment per label in rheumatology clinics and private practices. Primary endpoint was the change in PROs [EuroQol-5 Dimensions-3 Levels (EQ-5D-3L) questionnaire, Health Assessment Questionnaire Disease Index (HAQ-DI), and Work Productivity and Activity Index for RA (WPAI:RA)] after 12 months of treatment. Other endpoints included Disease Activity Score for 28 joints with erythrocyte sedimentation rate (DAS28-ESR), healthcare resource utilization, and golimumab adherence. Changes in continuous variables from baseline were evaluated with the paired t test. One hundred forty-five patients were recruited. The mean [standard deviation (SD)] EQ-5D-3L index increased significantly at 12 months versus baseline [from 0.427 (0.206) to 0.801 (0.229); p < 0.0001], with changes as early as 3 and 6 months (both p < 0.0001). Accordingly, there were statistically significant changes in all WPAI:RA domains from baseline to 3, 6, and 12 months (p < 0.0001). Patients' function improved gradually from the third month until the end of follow-up (p < 0.0001 for all time-points). Thirty (27.3%) and 60 (54.6%) patients achieved remission (DAS28-ESR < 2.6) and low disease activity (DAS28-ESR ≤ 3.2), respectively, at 12 months. Adherence rate to golimumab was high (mean [SD] 90.3% (7.5) at 12 months). In patients with moderate-to-severely active RA, golimumab significantly improved HRQoL, physical function, and work productivity and activity, with improvements in disease activity over 12 months in real-world settings.

Health outcomes and unmet needs in patients with long-standing rheumatoid arthritis attending tertiary care in Greece: a cohort study.

BACKGROUND: No previous studies have characterized a patient's experience of rheumatoid arthritis (RA) management in Greece and unmet needs may exist despite a broad range of available treatments. Therefore, we assessed quality of life (QoL), functional ability, and healthcare resource utilization in patients with established RA and receiving treatment in a tertiary care setting in Greece. METHODS: This was a prospective, observational cohort of patients aged ≥18 years, receiving any type of treatment for RA, and followed for 12 months at 7 rheumatology referral centers across mainland Greece (NCT01001182). Patient data were collected at the initial visit and 3, 6, and 9 months. QoL was evaluated using the Euro Quality of Life-5 dimensions questionnaire (EQ-5D) and functional ability was evaluated using the Health Assessment Questionnaire (HAQ). RESULTS: A total of 210 patients with RA were enrolled (76.7% women, mean ± standard deviation [SD] age: 59.1 ± 12.6 years, median [interquartile range] disease duration: 11.9 [5.0-16.0] years). Baseline mean ± SD EQ-5D and HAQ scores were 0.57 ± 0.32 and 0.75 ± 0.63, respectively, and remained largely unchanged throughout the study. Post-hoc comparison showed that patients receiving non-biologic disease-modifying antirheumatic drugs (non-bDMARDs) had significantly higher EQ-5D and lower HAQ-DI scores compared with those receiving biologic DMARDs. A majority of patients reported having difficulty doing housework or other duties (61.4 and 61.9%, respectively), and 55.2% reported needing external support for these tasks. Positive correlation was observed between QoL and functional ability. Hospitalization at least once during the study occurred in 9.5% of the patients, and 12.5% of these cases were due to exacerbation of RA. At baseline, 52.4% of the patients were retired, with 38.5% of retirees having retired early due to RA. Among the patients who were retired at baseline, the mean ± SD period from actual retirement to expected retirement age was 12.1 ± 8.1 years. CONCLUSION: QoL and functional ability were positively correlated in patients with long-standing RA, with a large proportion showing impairments in both. Timely, target-oriented treatment initiated as soon as possible after diagnosis may help to improve patient-reported outcomes and limit the burden of RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01001182 . Registered 23 October 2009.

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.

Longterm Beneficial Effect of Canakinumab in Colchicine-resistant Familial Mediterranean Fever.

OBJECTIVE: To assess the efficacy and safety of the interleukin-1ß (IL-1ß) inhibitor canakinumab in all adolescent and adult patients with familial Mediterranean fever (FMF) identified from the Greek National Registry for off-label drug use between 2010 and 2015. METHODS: In this retrospective longitudinal outcome study, clinical and laboratory data were collected from 14 patients (7 men) aged median 38.5 years (range 13-70), with median disease duration of 14 years, and active FMF despite colchicine (n = 9) or both colchicine and anakinra (n = 5). RESULTS: All patients continued to receive canakinumab at last visit (median of 18 mos, range 13-53), which was initially given as monotherapy (n = 8) or in combination with colchicine and/or corticosteroids, every 4 (n = 7), 6 (n = 2), or 8 weeks (n = 5). Eleven patients (79%), including 6 receiving monotherapy, achieved complete clinical remission within 2 months (median), while normalization of all laboratory variables denoting inflammation occurred in 92% at 3 months (median). The remaining 3 patients achieved partial responses. Responses were sustained in all but 4 patients, who relapsed. Reducing the canakinumab administration interval from 8 or 6 weeks to 4 weeks led to suppression of disease activity in the relapsing patients. On the other hand, drug administration interval could be safely increased in 2 patients in remission. Corticosteroid doses were significantly reduced during followup. Canakinumab was well tolerated; 1 patient experienced a urinary tract infection and another one a viral gastroenteritis. CONCLUSION: Treatment with canakinumab in an individualized dosing scheme results in rapid and sustained remission in colchicine-resistant FMF.

The effect of non-steroidal anti-inflammatory drugs on matrix metalloproteinases levels in patients with osteoarthritis.

OBJECTIVE: The objective of this study is to determine and comparatively evaluate the effects of three different non-steroidal anti-inflammatory drugs on the levels of metalloproteinases MMP-1, MMP-3 and MMP-8, as well as on their tissue inhibitor TIMP-1, in patients suffering from idiopathic osteoarthritis. The effect of these drugs on the articular cartilage and the probable use of MMPs and TIMP-1 as markers of disease and treatment was also investigated. METHODS: Thirty-six patients with OA were selected and allocated to three groups on the basis of their disease location. All patients received anti-inflammatory treatment with special selective COX-2 inhibitors, i.e. celecoxib, meloxicam, aceclofenac. Each drug was given to every patient for three months following a randomized order of administration. Serum levels of MMP-1, MMP-3, MMP-8 and TIMP-1, and ratios MMP-1/TIMP-1, MMP-3/TIMP-1, MMP-8/TIMP-1 were measured before and after treatment. RESULTS: The use of aceclofenac resulted in no significant variation in either MMPs concentration and MMPs/TIMP-1 ratio. This outcome concerns the three groups and the 36 patients that form them. After all patients had received all three NSAIDs, MMPs and TIMP-1, these parameters were compared to their initial and final median values. A significant reduction in MMP-3 was found so in all OA patients as in the group of knee OA patients. CONCLUSIONS: 1. Of the MMPs studied, MMP-3 levels were found to be significantly reduced after NSAIDs treatment. Therefore, serum MMP-3 levels in OA patients could be proven to be a useful evaluating marker of treatment on the cartilage level. 2. No significant differences were observed among NSAIDs administered with regards to their effect on MMPs and TIMP-1 concentration.

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.

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.

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.

Biomarkers in systemic sclerosis-related pulmonary arterial hypertension.

Systemic sclerosis (SSc) is a complex multisystem disease characterized by vascular involvement and generalized disturbance of the microcirculation. Pulmonary vascular disease leads to systemic sclerosis-related pulmonary arterial hypertension (SScPAH). SScPAH is a devastating complication with a considerable impact on prognosis, being a common cause of disease-related death. The ability to detect this process at an early stage by simple means would be of great value, since effective treatment is now available. There is increasing evidence that several biomarkers increase in proportion to the extent of right ventricular dysfunction and correlate with hemodynamic, echocardiographic and functional measurements of pulmonary vascular disease. Biomarkers may be used to identify high-risk patients for more invasive procedures, provide prognostic information, and guide vasodilator therapy. In this article, we review potential biomarkers in SScPAH as tools for screening, diagnostic evaluation, risk stratification, prediction of disease severity and indicators of treatment efficacy.

Significance of serum uric acid in pulmonary hypertension due to systemic sclerosis: a pilot study.

Systemic sclerosis is a connective tissue disease, which may lead to elevated pulmonary arterial pressure due to pulmonary arterial hypertension and/or left ventricular diastolic dysfunction. Uric acid (UA) has been shown to be elevated in patients with pulmonary hypertension (PH) and heart failure. We aimed to investigate the potent relationship between serum UA and pulmonary pressure as well as functional capacity in patients with SSc. We studied 66 patients (mean age 57.7±12.1years, 63 women), presenting with SSc. Systolic pulmonary artery pressure assessed by echocardiography, lung function tests, six-minute walk test (6MWT) and serum UA levels were recorded in all patients. In 24 (36%) patients, the diagnosis of PH was established by echocardiography (systolic pulmonary artery pressure ≥40 mmHg). Patients with PH had higher UA serum levels compared to patients without PH (5.1±2.1 mg/dl vs. 4.2±0.9 mg/dl, p=0.04). Among patients with PH, UA values were inversely correlated with the SMWT distance (r=-0.51, p=0.01). Serum UA values increased in proportion to the functional capacity in PH patients with scleroderma. Further investigations in prospective studies will unfold in detail the pathophysiological significance of UA in SSc patients with PH and determine its role as a prognostic marker in the assessment and monitoring of the disease.

Left atrial volume and N-terminal pro-B type natriuretic peptide are associated with elevated pulmonary artery pressure in patients with systemic sclerosis.

Early detection of pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) is essential as it leads to substantial morbidity and mortality irrespective of its etiology. The aim of our study was to determine whether noninvasive biochemical and/or echocardiographic indices can predict the presence of PH in these patients. We prospectively studied 66 patients (mean age of 57.7 +/- 12.1 years, 63 women) with SSc without clinical manifestations of heart failure. All patients underwent standard and tissue Doppler echocardiography. Plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) levels were also measured. In 24 (36%) patients, the diagnosis of PH was established by echocardiography (systolic pulmonary artery pressure value > or =40 mmHg). Left atrial (LA) volume, NT-proBNP, ADMA, ratio of early transmitral filling velocity to early diastolic velocity of the mitral annulus (mitral E/E (m)), and right ventricular myocardial performance index (MPI) were univariate predictors of PH. In multivariate analysis, NT-proBNP, LA volume, and right ventricular MPI were independent predictors of PH in SSc patients. LA volume and NT-proBNP may be useful noninvasive markers for the prediction of elevated pulmonary artery pressure in patients with SSc. These parameters should be considered when assessing this population for risk stratification and for identification of patients demanding further investigation and institution of specific therapy for the disease at the time when it is most likely to be effective.

Early detection of cardiac involvement in systemic sclerosis assessed by tissue-Doppler echocardiography: relationship with neurohormonal activation and endothelial dysfunction.

OBJECTIVE: Cardiopulmonary complications are common in patients with systemic sclerosis (SSc). We assessed cardiac involvement in patients with SSc using echocardiography and investigated the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) with echocardiographic measures of myocardial function in sera of patients with SSc who had no symptoms of heart failure. METHODS: We prospectively studied 52 patients with SSc (mean age 55.7 +/- 10.1 yrs, 51 women), with conventional and tissue-Doppler echocardiography. Plasma NT-proBNP and ADMA levels were measured in all patients. Data were compared with those obtained from 25 healthy controls comparable for age and sex. RESULTS: Patients with SSc had impaired left ventricular (LV) and right ventricular diastolic function expressed by inverted ratio of peak early to peak late transmitral (Mit E/A) and transtricuspid velocity and increased left atrial diameter compared with controls. Peak systolic mitral lateral annular motion velocity and peak early diastolic mitral lateral annular motion velocity (LV Em) were lower, while LV E/Em ratio was higher, in patients with SSc compared to controls. ADMA was significantly related with LV Em and E/Em ratio. NT-proBNP was associated with Mit E, Mit E/A ratio and mitral deceleration time. Significant correlation was also observed between NT-proBNP and ADMA levels. CONCLUSION: Depressed cardiac function is common, even in asymptomatic patients with SSc. NT-proBNP and ADMA are significantly correlated with echocardiographic abnormalities, providing a potent link for cardiac function, neuroendocrine derangement, and endothelial dysfunction in patients with SSc who have cardiac disease.

N-terminal probrain natriuretic peptide as a biochemical marker in the evaluation of bosentan treatment in systemic-sclerosis-related pulmonary arterial hypertension.

The purpose of our study was to investigate the effect of bosentan treatment on surrogate markers in patients with systemic-sclerosis-related pulmonary arterial hypertension (SScPAH). We studied ten SScPAH patients (nine female, median age 58 years, median duration of disease 9 years). Six-minute walk test (SMWT) and plasma N-terminal probrain natriuretic peptide (NT-proBNP) levels were recorded from patients at baseline and after 20 weeks under bosentan treatment. Wilcoxon paired signed rank test was applied in order to compare NT-proBNP levels and SMWT at baseline and week 20. At week 20, NT-proBNP levels were decreased from a median of 474 fmol/ml (range, 212-1407 fmol/ml) at baseline to 238 fmol/ml (range, 198-335 fmol/ml; p=0.002). Mean SMWT distance increased from a baseline median value of 323 m (range, 224-368 m) to 372 m (range, 232-530 m), representing a nonsignificant increase. Our results suggest that NT-proBNP is a biochemical surrogate marker, which could be used to evaluate the effects of bosentan or other vasodilation therapy in SScPAH.