Low-dose aspirin as primary prophylaxis for cardiovascular events in systemic lupus erythematosus: a long-term retrospective cohort study.

OBJECTIVES: Cardiovascular (CV) morbidity and mortality are significantly greater in SLE patients than in the general population. ASA is known to be associated with a decrease in the incidence of CV events in high-risk patients from the general population, but its efficacy as primary prophylaxis in SLE patients has not yet been investigated. METHODS: The clinical charts of SLE patients consecutively admitted to a tertiary centre who, at admission, satisfied 1992 ACR and/or 2012 SLICC classification criteria for SLE and had not experienced any CV event, were reviewed. The occurrence of any CV event was recorded at each visit. ASA was prescribed to all patients at first visit. The rate and reasons for ASA discontinuation were also recorded at each visit. RESULTS: One hundred and sixty-seven consecutive SLE patients were enrolled and followed up for a median of 8 years (range 1-14 years). Among them, 146 regularly took the medication (ASA-treated patients) and 21 refused to take or discontinued it (non-ASA-treated patients). Five CV events occurred in the 146 ASA-treated patients (4.2 per 1000 person-years) and four in the 21 non-ASA-treated patients (30 per 1000 person-years; P = 0.0007). The CV event-free rate was higher in ASA-treated than in non-ASA-treated patients (log-rank test χ(2) = 15.74; P = 0.0001). No relevant side-effect related to ASA was recorded. CONCLUSION: Low-dose ASA is a safe treatment and may be beneficial in the primary prophylaxis of CV events in SLE patients. Controlled, prospective studies are needed to provide a better definition of its role in these patients.

Clinical profile and direct medical cost of care of adults presenting with systemic lupus erythematosus in Italy.

OBJECTIVES: To determine the clinical profile and estimate the annual direct medical cost of care of adult patients with active, autoantibody positive systemic lupus erythematosus (SLE) in Italy. METHODS: A two-year, retrospective, multicentre, observational study was conducted from January to May 2011. Patients' characteristics, SLE disease activity and severity, rate of flares, healthcare consumption (e.g. medications, etc.) were evaluated. Medical costs were assessed from the Italian National Health Insurance perspective. RESULTS: Four centres enrolled 96 eligible patients, including 85.4% women. Patients were equally stratified per disease severity (severe SLE: 51%). The mean (SD) age was 42.9 (13.8) years. At baseline, SLE duration was 12.6 (7.2) years. The mean (SD) SELENA-SLEDAI score was higher in severe than in non-severe patients 9.2 (6.4) vs. 3.3 (3.1) (p<0.001). The mean (SD) SLICC/ACR index score was similar in the two subgroups: 0.4 (0.8) vs. 0.3 (0.8). Over the study period, severe patients experienced on average 0.73 (0.56) flares/year and non-severe patients 0.57 (0.63). The annual medical cost was 1.6 times higher in severe than in non-severe patients (€2,101 vs. €1,320; p=0.031). The cost of medications was also 2.5 times higher in severe patients (€1101 vs. €445, p=0.007). Low C3/C4 complement levels and each severe flare incremented the annual cost of €550 (p=0.011) and €465 (p=0.02), respectively. CONCLUSIONS: The medical cost of SLE in Italy is related to disease severity and flares. Medications identified as the main cost drivers, and low C3/C4 complement levels and severe flares as the main cost predictors, increased significantly the cost of SLE management.

Safety of etanercept and methotrexate in patients with rheumatoid arthritis and hepatitis C virus infection: a multicenter randomized clinical trial.

OBJECTIVE: To evaluate the safety and efficacy of therapy with etanercept and methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and mild hepatitis C virus (HCV) infection. METHODS: In this prospective open study, 29 patients with active RA were randomly assigned to receive therapy with MTX alone, etanercept alone, or a combination of MTX and etanercept, and monitored up to 54 weeks. The primary endpoint was safety; secondary aims were efficacy as defined by the 44-joint Disease Activity Score (DAS44) and health assessment questionnaire (HAQ). Serum liver enzymes and HCV viral load were serially measured. RESULTS: In the whole cohort, aspartate aminotransferase (AST) serum levels were (mean ± SD) 35 ± 3 at entry, 39 ± 5, 41 ± 7, and 38 ± 4 at 14, 30, and 54 weeks, respectively; alanine aminotransferase (ALT) serum levels were 43 ± 5 at entry, 47 ± 5, 53 ± 9, and 50 ± 6 at 14, 30, and 54 weeks, respectively. HCV viral load was 5.6 ± 0.5 at entry, 5.9 ± 0.6, 5.7 ± 0.3, and 5.6 ± 0.6 at 14, 30, and 54 weeks, respectively. AST and ALT did not significantly change in all 3 arms of treatment, nor did HCV viral load. A significant reduction of DAS44 (p < 0.01) and HAQ (p < 0.04) was detected at 54 weeks compared to baseline. No patient discontinued the therapy because of worsening of liver disease. CONCLUSION: This study showed that patients with RA and chronic HCV and mild hepatitis may be successfully treated with etanercept and MTX without increasing the risk of hepatotoxicity and HCV replication. ClinicalTrials.gov Identifier NCT01543594.

Relationship of focal erosions, bone mineral density, and parathyroid hormone in rheumatoid arthritis.

OBJECTIVE: To investigate the relationship among focal bone erosions and bone mineral density (BMD), 25(OH) vitamin D (25OHD), and parathyroid hormone (PTH) values in patients with rheumatoid arthritis (RA). METHODS: The study included 1191 RA patients (1014 women, 177 men, mean age 58.9 ± 11.1 yrs) participating in a multicenter, cross-sectional study. RESULTS: Radiographic evidence of typical bony erosions on hands or forefeet was found in 64.1% of patients. In those with bone erosions as compared to those without, mean BMD Z score values were significantly lower at both the spine (-0.74 ± 1.19 vs -0.46 ± 1.31; p = 0.05) and the hip (-0.72 ± 1.07 vs -0.15 ± 1.23; p < 0.001). In the subgroup of patients not taking vitamin D supplements, PTH levels were significantly higher in those with erosive arthritis (25.9 ± 14.0 vs 23.1 ± 11.6 pg/ml; p = 0.01); whereas the 25OHD concentrations were very similar in the 2 groups. The mean differences for BMD and PTH among the erosive and nonerosive RA remained statistically significant when values were simultaneously adjusted for all disease and mineral metabolism factors (i.e., age, sex, menopause, disease duration, Disease Activity Score 28-joint count, Health Assessment Questionnaire, activities of daily living, Steinbrocker functional state, glucocorticoid therapy, body weight, and bisphosphonate treatment). CONCLUSION: Our results suggest that the presence of bone erosions in RA correlates with low BMD levels and high PTH levels, and that these associations are independent of the degree of functional impairment and other common determinants of bone mass and mineral metabolism in adults with RA. These findings suggest that treatments to prevent bone loss or suppress PTH levels might positively affect the progression of bone erosions in RA.

Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability.

INTRODUCTION: The aim of this study was to estimate the prevalence and determinants of vitamin D deficiency in patients with rheumatoid arthritis (RA) as compared to healthy controls and to analyze the association between 25-hydroxyvitamin D (25(OH)D) with disease activity and disability. METHODS: The study includes 1,191 consecutive RA patients (85% women) and 1,019 controls, not on vitamin D supplements, from 22 Italian rheumatology centres. Together with parameters of disease activity, functional impairment, and mean sun exposure time, all patients had serum 25(OH)D measured in a centralized laboratory. RESULTS: A total of 55% of RA patients were not taking vitamin D supplements; the proportion of these with vitamin D deficiency (25(OH)D level <20 ng/ml) was 52%. This proportion was similar to that observed in control subjects (58.7%). One third of supplemented patients were still vitamin D deficient. In non-supplemented RA patients 25(OH)D levels were negatively correlated with the Health Assessment Questionnaire Disability Index, Disease Activity Score (DAS28), and Mobility Activities of daily living score. Significantly lower 25(OH)D values were found in patients not in disease remission or responding poorly to treatment, and with the highest Steinbrocker functional state. Body mass index (BMI) and sun exposure time were good predictors of 25(OH)D values (P < 0.001). The association between disease activity or functional scores and 25(OH)D levels remained statistically significant even after adjusting 25(OH)D levels for both BMI and sun exposure time. CONCLUSIONS: In RA patients vitamin D deficiency is quite common, but similar to that found in control subjects; disease activity and disability scores are inversely related to 25(OH)D levels.

Insulin resistance is an independent risk factor for atherosclerosis in rheumatoid arthritis.

The objective of this study was to investigate the relationship between insulin resistance (IR) and subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Carotid artery intima media thickness (IMT), using ultrasound evaluation, and other clinical and laboratory variables were investigated in 45 RA outpatients and in 48 controls with soft tissue disorders. IR was assayed by homeostasis model assessment (HOMA2) and metabolic syndrome by National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) criteria. Insulin resistance, as defined by HOMA2-IR>1, was seen in 40 (88.9%) RA patients and in three (6.2%) controls (p<0.001). No significant difference was detected in the prevalence of metabolic syndrome. The median IMT was greater in RA patients (0.76 mm; interquartile range [IQR] 0.65, 0.85) than in the controls (0.66 mm; IQR 0.60, 0.72) (p<0.001). Dividing the RA patients according to the cut-off IMT value (0.72 mm), a difference was detected in both systolic (p=0.04) and diastolic blood pressure (p=0.02), disease activity score (DAS28) (p=0.008), HOMA2-IR (p<0.001) and cumulative oral steroid dose (p=0.001). Moreover, the frequency of cases with increased IMT was higher in glucocorticoid users than in non-users (21/23 vs. 9/22, respectively) (p<0.001). Spearman's rho correlation showed a significant positive relationship between IMT and HOMA2-IR (p<0.001). Multivariate stepwise analysis selected HOMA2-IR plus diastolic BP plus glucocorticoid exposure as the best predictive model for subclinical atherosclerosis (R2c=0.577, F=21, p<0.001). In conclusion, this study showed a significantly higher prevalence of IR in RA patients and pointed out a significant association between IR and subclinical atherosclerosis. This relationship may be driven primarily by exposure to steroid therapy.

High prevalence of metabolic syndrome in patients with ankylosing spondylitis.

The objective of this work is to investigate the occurrence of atherosclerosis and metabolic syndrome (MetS) in ankylosing spondylitis (AS) patients (pts). Twenty-four consecutive AS pts (men, 87.5%; median age, 50.5 years; median disease duration, 16.5 years), fulfilling the modified 1984 New York criteria for AS criteria, and 19 age- and sex-matched controls were investigated. Clinical atherosclerosis was evaluated by physical examination for cardiovascular (CV) diseases and history or drug use for CV events. Subclinical atherosclerosis was detected by mean intima media thickness (a-IMT) and maximum IMT (max-IMT) of carotid arteries using ultrasonography. Laboratory investigations including fasting plasma glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides were assessed by standard methods, while homocysteine was assessed by chemiluminescence. MetS was assessed using the updated NCEP-ATP III criteria. Disease activity was defined according to the International Ankylosing Spondylitis Assessment Study criteria. The 10-year CV risk (%) profile was evaluated in agreement to the Progetto Cuore criteria. No major CV event was detected in the study population. No significant differences were found when AS pts and controls were compared according to the mean a-IMT (0.52+/-0.26 vs 0.51+/-0.13 mm), max-IMT (0.92+/-0.20 vs 0.85+/-0.39 mm), prevalence of abnormal max-IMT >1 mm (27.2 vs 5.3%), and 10-year CV risk (9.9+/-9.6 vs 3.6+/-1.8%). Systolic blood pressure (p=0.04), triglyceride to HDL cholesterol ratio (p=0.002), and LDL cholesterol (p=0.03) were found significantly higher in AS pts than in controls; on the contrary, HDL cholesterol was pointed out as significantly lower (p<0.001). MetS was found in 11/24 (45.8%) AS pts and in 2/19 (10.5%) controls (p=0.019). No significant relationship emerged in MetS prevalence among AS pts regarding the mean value of age, disease duration, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Disease Activity Index, and the Italian version of Health Assessment Questionnaire. This preliminary report points out a higher prevalence of MetS in AS pts than in controls. Further studies are needed to confirm this finding.

[A comparison between the Simplified Disease Activity Index (SDAI) and the Disease Activity Score (DAS28) as measure of response to treatment in patients undergoing different therapeutic regimens]. / Analisi dei rapporti tra SDAI (Simplified Disease Activity Index) e DAS28 (Disease Activity Score) in pazienti sottoposti a differenti terapie di fondo.

OBJECTIVE: To compare the SDAI values to DAS28 scores in RA patients undergoing different DMARD regimens. METHODS: The SDAI is an unweighted numerical sum of five outcome parameters: tender and swollen joint count (based on 28-joint assessment), patient and physician global assessment of disease activity (visual analogue scale: 0-10 cm) and level of C-reactive protein (mg/dl). 80 patients (F/M 68/12; age between 20-68 years, median 52) with active rheumatoid arthritis were prospectively enrolled in the study. The patients were randomly assigned to one of four groups according to the therapeutic regimens: group I: Methotrexate (MTX) 15 mg/weekly + salazopyrin 2 g/daily; group II: MTX 15 mg/weekly + infliximab 3 mg/Kg at time 0, 2, 4 and every 8 weeks; group III: MTX 15 mg/weekly + etanercept 25 mg/twice weekly; group IV: MTX 15 mg/weekly + adalimumab 40 mg/every other week. SDAI and DAS28 were determined at baseline and after 6 months in each patient. Mean changes in SDAI values were compared to those detected in DAS 28 at baseline and after 6 months. RESULTS: SDAI and DAS 28 were found to be significantly correlated at baseline. Moreover, changes in SDAI over time paralleled those in DAS, and were found to be significantly correlated. CONCLUSIONS: SDAI is a valid measure of response to treatment in RA patients undergoing different therapeutic regimens.

Echocardiographic alterations in systemic sclerosis: a longitudinal study.

OBJECTIVE: To investigate the evolution of cardiac alterations in systemic sclerosis (SSc). METHODS: Echocardiographic and echo-Doppler findings from 77 unselected SSc patients were analyzed at the first clinical observation and after a follow-up period of 65 +/- 36 months. Data were compared with those obtained from 45 normal subjects matched for age and sex. RESULTS: Baseline left ventricular (LV) systolic function was normal in all patients and controls while LV diastolic dysfunction (expressed by an inverted E/A ratio which represents early and late filling of the LV during atrial contraction) was present in 23 patients and in 1 control ( P < 0.001). At the end of the follow-up period, while LV systolic function declined in 1 case alone, 6 further patients developed an inverted E/A ratio. Moreover, in the group of SSc patients mean A-wave values, E/A ratio, left atrial dimension, and LV wall thickness significantly changed, all indicating the progression of heart involvement. The alteration of LV diastolic function was independent of other known causes potentially affecting LV relaxation. Moreover, impairment of LV filling parameters was detected in the first phase of follow-up, while the anatomical changes occurred in the last phase. CONCLUSIONS: Our data confirm the significant prevalence of LV diastolic dysfunction in SSc patients and the role of primary myocardial involvement. The long-term follow-up demonstrates that LV filling dysfunction is progressive and precedes the occurrence of LV remodeling.

The arthropathy of systemic sclerosis: a 12 month prospective clinical and imaging study.

OBJECTIVE: To assess the clinical and radiological features of systemic sclerosis (SSc) joint involvement in a prospective cross-sectional study. DESIGN AND PATIENTS: Seventy-six consecutive patients with SSc divided into clinical and serological subsets were investigated. Clinical and radiological assessments of the hands and feet were carried out. Three radiological patterns of inflammatory, degenerative and fibrotic changes were predefined. The Health Assessment Questionnaire (HAQ) disability index (DI) and individual components of the HAQ-DI were also evaluated. RESULTS: The highest impairments on the HAQ-DI (median 0.44; range 0-2.87) were detected in subdimensions such as hygiene, grip and activity components. Clinically articular involvement, arthralgia and finger contractures were seen more frequently than arthritis, and a significantly higher prevalence of finger flexion was found in patients with diffuse cutaneous SSc (P=0.03) compared with the other SSc subtypes. Radiologically, distal interphalangeal joint space narrowing and flexion deformity indicating periarticular fibrosis were frequently detected. Juxta-articular osteoporosis, joint space narrowing and flexion contractures of the fingers were seen significantly more frequently in the hands. A significantly higher frequency of fibrotic pattern were found in the hands whereas a degenerative pattern was more frequent in the feet (P<0.05). Finally, significant correlations were detected between flexion contractures and a radiological fibrotic pattern (P<0.001), and the severity scores of peripheral vascular impairment (P=0.026) and skin (P=0.007). CONCLUSION: This cross-sectional prospective study confirms that an arthropathy is common in SSc patients and shows that it is a major determinant of disability. A classification of radiological alterations into three specific patterns is proposed.

Successful neridronate therapy in transient osteoporosis of the hip.

We report on an uncommon case of bilateral transient osteoporosis of the hip (TOH) occurring in a young woman during pregnancy. The clinical features and the therapeutic action of intramuscular neridronate sodium, a third-generation amino-bisphosphonate, are underlined.

Low-dose intravenous cyclophosphamide in systemic sclerosis: a preliminary safety study.

Both oral and intravenous high-dose cyclophosphamide (CYC) regimens are associated with serious side effects when used for the treatment of systemic sclerosis (SSc). The aim of the present trial was to test the safety of low-dose intravenous CYC in patients with SSc. Eight SSc patients, in whom CYC treatment was warranted, were studied at baseline and after 6 months' intravenous CYC treatment (500 mg pulses at weeks 0, 1, 2, 6, 10, 14, 18 and 22). Side effects probably related to CYC treatment were carefully investigated. The development of amenorrhea was assessed during the period of treatment and over the following 12 months. The therapy was well tolerated overall. No patient discontinued treatment because of side effects. Leukopenia, premature ovarian failure, hemorrhagic cystitis, microscopic hematuria and liver toxicity were never detected. The most common adverse events were mild and self-limiting nausea and weakness. Our data suggest that low-dose intravenous CYC is relatively safe, at least in the short term. Further studies are needed to assess both the efficacy and the long-term safety.

Cross-sectional evaluation of YKL-40 serum concentrations in patients with systemic sclerosis. Relationship with clinical and serological aspects of disease.

OBJECTIVE: To investigate the behavior of serum YKL-40 in a cohort of patients with systemic sclerosis (SSc). METHODS: Forty SSc patients (35 women, 5 men) were investigated for serum YKL-40, soluble interleukin 2 receptor alpha (sIL-2Ra; by ELISA), von Willebrand factor (vWF; ELISA), and aminoterminal propeptide of type III procollagen (PIIINP; radioimmunoassay) concentrations. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were evaluated. Skin and organ system involvement were scored according to the Medsger organ/system severity scale. RESULTS: Serum YKL-40 in SSc patients (mean 132.9 ng/ml; median 75.5, 95% CI 87.8-175) was significantly higher than in controls (mean 66.6 ng/ml; median 52, 95% CI 54.6-78.6). Fourteen patients had levels > 135 ng/ml (cutoff value) with a mean of 264.7 +/- 160 ng/ml. Serum YKL-40 values were found to be more frequently increased in patients with arthralgias/arthritis (18 cases) than in patients without such features (4/22) (p = 0.021). Significant differences were found comparing serum YKL-40 concentrations in the patients with or without joint involvement (median 138 vs 57.5 ng/ml, respectively; p = 0.007). Serum YKL-40 levels correlated with the joint involvement severity score (p = 0.018) and sIL-2Ra levels (p < 0.001). No differences were found with any therapeutic regimen. CONCLUSION: This preliminary study shows that YKL-40 serum levels are increased in SSc and that they are correlated with sIL-2Ra and joint involvement, suggesting a relationship with cartilage and/or fibroblast activity.

Foot involvement in systemic sclerosis: a longitudinal study of 100 patients.

OBJECTIVE: To investigate the clinical and radiologic features of foot involvement in systemic sclerosis (SSc). PATIENTS: One hundred patients (91 women, 9 men; mean age, 51.9 +/- 11 years) with SSc (mean disease duration, 17.4 +/- 10.5 years) were retrospectively studied. Seventy-four subjects had limited scleroderma and 26 diffuse scleroderma. METHODS: Radiologic changes of foot involvement were assessed at presentation (time of diagnosis) and follow-up ranging from 1 to 28 years (median range, 7 years) and were compared with changes detected in the hands of each patient at the same presentation and follow-up. Correlations with skin and internal organ involvement were assessed. RESULTS: Ninety patients had foot involvement clinically. Forty-three had it at initial evaluation; 47 developed it during follow-up. Median time to clinical event occurrence was 10 years (95% CI, 6.7-13.3) with 44% censored case probability at this time. The onset of clinically evident foot involvement was later in limited SSc than in diffuse SSc. In comparison with hands with SSc, feet with SSc had lower rates of necrotizing Raynaud's phenomenon and tendon friction rubs and decreased skin thickening scores, whereas arthralgias occurred significantly more often. At presentation, 37 patients had radiologic abnormalities of their feet compared with 69 of their hands (P <.001); the hands had a significantly higher prevalence of acroosteolysis (P <.001). At the end of the follow-up, 35 of 50 SSc patients had radiographic foot involvement compared with 50 of 51 with hand involvement (P <.001). A significantly higher prevalence of acroosteolysis (P <.001), calcinosis (P <.05), and erosions (P <.05) of the hands were detected at that time. CONCLUSION: This study shows that compared with hand involvement in SSc, foot involvement in SSc has a later onset and is relatively less frequent but can be disabling.