Pulmonary hypertension in systemic lupus erythematosus: prevalence, predictors and diagnostic strategy.

OBJECTIVES: To investigate the prevalence and predictors of pulmonary hypertension (PH) in patients with systemic lupus erythematosus (SLE) and to validate a diagnostic strategy. METHODS: 245 patients with SLE entered a screening program. Possible PH was defined as two consecutive systolic pulmonary arterial pressure (PAP) values ≥ 40mmHg by echocardiography. The subsequent diagnostic procedure, including right heart catheterization if needed, confirmed or excluded the diagnosis of PH secondary to cardiopulmonary disease or SLE-related pulmonary arterial hypertension (PAH). Independent predictors of PH were identified by multivariant multiple linear or logistic regression models. The sensitivity (S), specificity (SP), positive (PPV) and negative predictive values (NPV) were calculated for different screening cutoff values. RESULTS: 88% patients were women. The mean (SD) age at the time of enrolment was 45 (16) years. 12 cases of PH were detected, all secondary, with a resulting prevalence of 5%. Two consecutive echocardiographic PAP measurements ≥ 40mmHg performed best as the cutoff point for screening (S 100%, SP 97%, PPV 70, NPV 100), as compared with single PAP measurements ≥ 30mmHg or ≥ 40mmHg The age at the time of enrolment was the only variable independently associated with PAP values (p=0.0001), with the SLICC damage index score showing a borderline association (p=0.08). Only the age at the time of enrolment showed an independent association with PH (OR 1.10, 95% CI 1.06-1.17). CONCLUSION: We found a low prevalence of PH. Screening echocardiograms in asymptomatic lupus patients are thus not recommended. Two consecutive PAP values ≥ 40mmHg by echocardiogram is the best screening cutoff for starting investigations in SLE patients with suspected PH.

Infectious complications of chemotherapy in clinically aggressive mature B and T cell lymphomas.

BACKGROUND: Scientific literature on infectious complications of chemotherapy in lymphomas is often based on retrospective studies or clinical trials performed with selected patients. This population may not be representative of the routine clinical practice. We aimed to analyse the incidence and type of infections associated to standard chemotherapy in clinically aggressive mature B and T cell lymphomas (AMBTL) and to detect baseline variables predictive of the risk of infection in a cohort of unselected patients. METHODS: A prospective observational study of all the patients treated with first line chemotherapy for AMBTL in our Lymphoma Unit, in the setting of a community based teaching hospital, was performed. The statistical methods were univariate and multivariate analyses. RESULTS: 183 infectious episodes were registered in 97 (49%) of the 198 patients. Seventy-nine of them (43%) were associated to febrile neutropenia (27% of the patients). Microbiological documentation was obtained in 46% and only clinical documentation in 15%; 39% were classified as fever of unknown origin. Gram negative bacilli were the predominant aetiology. There were several variables related to risk of infection, but in multivariate analysis only a poor initial performance status was predictive of the risk of febrile neutropenia and infection during the first line chemotherapy. CONCLUSIONS: In our cohort of AMBTL patients treated with first line chemotherapy, more than half of the relevant infections occurred without febrile neutropenia. A poor performance status was the only independent variable associated with the risk of febrile neutropenia or infection in the course of first line chemotherapy.

Prognostic factors in follicular lymphoma: the importance of beta-2 microglobulin.

AIMS AND BACKGROUND: The Follicular Lymphoma International Prognostic Index (FLIPI) is a useful tool for the prognostic assessment of follicular lymphoma but beta-2 microglobulin (B2M) was not incorporated in this index. We aimed to compare the predictive value of B2M, FLIPI and other prognostic factors not included in the FLIPI index for overall survival (OS), complete remission (CR), and time to treatment failure (TTF) in a nonselected follicular lymphoma series. METHODS AND STUDY DESIGN: Retrospective univariate and multivariate analysis of the prognostic value (for OS, CR, TTF) of B2M, FLIPI and other prognostic variables in follicular lymphoma was conducted in a cohort of follicular lymphoma patients between 1987 and 2007. RESULTS: One hundred and six patients were studied. In univariate analysis B2M and B symptoms were significantly associated with OS, and FLIPI only detected two risk levels. In multivariate analysis of OS only two significant variables were found: FLIPI and B2M. Multivariate analysis of CR showed that normal B2M, absence of a bulky mass, uninvolved bone marrow, and chemotherapy with rituximab were significant predictors of CR. FLIPI (three levels), B2M, bone marrow infiltration, and chemotherapy with rituximab were significantly associated with TTF. CONCLUSIONS: We found a high predictive value of B2M for OS, CR, and TTF. B2M and FLIPI were the most important variables to predict OS. However, in our series FLIPI differentiated only between two mortality risk levels.

Changes in vitamin D levels in patients with systemic lupus erythematosus: Effects on fatigue, disease activity, and damage.

OBJECTIVE: To analyze whether changes in serum 25-hydroxyvitamin D (25[OH]D) levels affect activity, irreversible organ damage, and fatigue in systemic lupus erythematosus (SLE). METHODS: We performed an observational study of 80 patients with SLE included in a previous cross-sectional study of 25(OH)D, reassessed 2 years later. Oral vitamin D(3) was recommended in those with low baseline 25(OH)D levels. The relationship between changes in 25(OH)D levels from baseline and changes in fatigue (measured by a 0-10 visual analog scale [VAS]), SLE activity (measured by the Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), and irreversible organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) were analyzed. RESULTS: Sixty patients took vitamin D(3). Mean 25(OH)D levels increased among all treated patients (P = 0.044), in those with baseline vitamin D levels <30 ng/ml (P < 0.001), and in those with baseline vitamin D levels <10 ng/ml (P = 0.005). Fifty-seven patients (71%) still had 25(OH)D levels <30 ng/ml and 5 (6%) had 25(OH)D levels <10 ng/ml. Inverse significant correlations between 25(OH)D levels and the VAS (P = 0.001) and between changes in 25(OH)D levels and changes in the VAS in patients with baseline 25(OH)D levels <30 ng/ml (P = 0.017) were found. No significant correlations were seen between the variation of the SLEDAI or SDI values and the variation in 25(OH)D levels (P = 0.87 and P = 0.63, respectively). CONCLUSION: Increasing 25(OH)D levels may have a beneficial effect on fatigue. Our results do not support any effects of increasing 25(OH)D levels on SLE severity, although they are limited by the insufficient 25(OH)D response to the recommended regimen of oral vitamin D(3) replacement.

Predictors of major infections in systemic lupus erythematosus.

INTRODUCTION: Infections commonly complicate the course of systemic lupus erythematosus (SLE). Our aim is to investigate the clinical predictors of major infections in patients with SLE. METHODS: A nested case-control study design was used within the prospective Lupus-Cruces cohort. The endpoints of the study were major infections. Cases were defined as patients with a major infection. Two controls (SLE patients without major infections), matched for time of follow-up until the event and age at diagnosis, were selected for each case. Univariate analysis and logistic regression models were used for the analysis of data. RESULTS: Two hundred and forty-nine patients (83 cases, 166 controls) were selected. Eighty-three episodes of major infections were analyzed; E. coli, S. aureus, M. tuberculosis and S. pneumoniae being the most frequent isolates. Univariate analysis identified several variables related with infection: lung and renal involvement, at or previous to the study point; leukopenia at the study point; antiphospholipid antibody-positivity and treatment with prednisone within 3 months previous to the study point, and the dose of prednisone received. Treatment with antimalarials, on the other hand, showed a strong inverse association with major infections. Logistic regression models identified treatment with antimalarials (odds ratio (OR) = 0.06, 95% confidence interval (CI) = 0.02 to 0.18), prednisone dose (OR = 1.12, 95% CI = 1.04 to 1.19) and lung involvement (OR = 4.41, 95% CI = 1.06 to 18.36) as significant and independent predictors of major infections. No significant interactions among these three variables were found. Further adjustment for potential confounders related with antimalarial treatment did not change the results. CONCLUSIONS: The risk of major infections in patients with SLE is mostly influenced by treatment. Prednisone treatment, even at moderate doses, increases the risk, whilst antimalarials have a protective effect.

Transiently positive anticardiolipin antibodies and risk of thrombosis in patients with systemic lupus erythematosus.

Fluctuations in the titers of anticardiolipin antibodies (aCL) have been reported in systemic lupus erythematosus (SLE) patients, but their relation with thrombosis is not completely understood. Prospective inception cohort of 237 patients with SLE (American College of Rheumatology criteria). Positivity for antiphospholipid antibodies (aPL) was defined according to Sapporo criteria. aCL was defined as persistently positive when more than two-thirds of the determinations were positive during follow-up. Patients were classified into four groups: A [positive lupus anticoagulant (LA)], B (negative LA and persistently positive aCL), C (negative LA and transiently positive aCL) and D (negative LA and aCL). Of these 237 patients, 211 (89%) patients were women. Median age at diagnosis and follow-up were 32 (2-78) and 10 (1-31) years, respectively; 33 (13.9%), 23 (9.7%), 42 (17.7%) and 139 (58.6%) patients were classified in groups A, B, C and D, respectively. Thirty (12.6%) and 23 (9.7%) patients suffered arterial and venous thrombotic events, respectively. Adjusted risk for arterial thrombosis was increased in groups A [odds ratio (OR) 15.69, 95% confidential interval (CI) 4.79-51.42, P < 0.001] and B (OR 7.63, 95% CI 2.00-29.08, P = 0.003), but not in group C when compared with group D. Adjusted risk of venous thrombosis was increased in group A (OR 4.24, 95% CI 1.36-13.20, P = 0.013), but not in groups B or C when compared with group D. Risk of thrombosis is not increased in SLE patients with negative LA and transiently positive aCL, even fulfilling Sapporo laboratory criteria, when compared with aPL-negative SLE patients.

Bicompartmental kinetics of tobramycin analysed with a wide range of covariates.

The pharmacokinetics of tobramycin was studied in adult patients (N = 151) admitted either for initial suspicion of Gram-negative infection or for prophylaxis. In addition to age, weight, height and creatinine clearance (CrCL), a range of other covariates were also analysed, including type of pathology, co-medication, fever, sex and ethnicity (Basque or not). All patients received 100mg tobramycin every 8 h and samples were collected at three time points after the first dose and at two time points after the fourth dose and assayed with a fluorescence polarisation immunoassay. The population mixed effects bicompartmental parameters were obtained from 725 concentration measurements using NONMEM, FOCE method, and were: systemic clearance, CL = 6.03 L/h (between-subject coefficient of variation (CV) %, 29.4%); volume of distribution, V = 15.04 L (7.3%); and intercompartmental constants, k(12) = 0.192 h(-1) (56%) and k(21) = 0.55 h(-1) (no CV% determined). Covariate modelling was performed within NONMEM. Two alternative significant covariate models (Models 1 and 2) are proposed, with functions of CrCL and/or sex (Model 2). However, for clinical purposes, differentiation by sex is insignificant. Model 1 is for CL = 3.1 + 0.05.CrCLL/h (17.3%); V = 14.6 L (12%); k(12) = 0.224 h(-1) (63%) and k(21) = 0.468 h(-1). Stochastic simulation was used to predict the expected concentration 95th percentiles after the recommended 7 mg/kg dose and for minimum inhibitory concentration (MIC) = 1 mg/L, as well as alternative once-daily dosing regimens for MIC = 2 mg/L. It is seen that once-daily high-dose tobramycin is an appropriate strategy with respect to pharmacodynamic indices, C(peak)/MIC or AUC/MIC (where C(peak) is the peak plasma concentration and AUC is the area under the concentration-time curve).

High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus.

BACKGROUND: Thrombosis is a frequent cause of morbidity and death in patients with systemic lupus erythematosus (SLE). Whether antiphospholipid syndrome (APS) is the cause of increased irreversible organ damage and mortality in lupus patients is not well established. METHODS: Prospective inception cohort of 202 patients with SLE (American College of Rheumatology criteria). Antiphospholipid syndrome was defined according to the Sapporo criteria. Irreversible damage was measured using the Systemic Lupus International Collaborating Clinics-American College of Rheumatology damage index (SDI) at 6 months and 1, 3, 5, 10, 15, 20, and 25 years after the diagnosis of SLE. All deaths were documented. RESULTS: A total of 88% of patients were women. Twenty-eight patients met criteria for definite APS. Mean (SD) follow-up was 9.7 (6.0) years. Nine patients could not be contacted for follow-up. All patients with APS experienced thrombosis, most of them in the arterial bed. Damage was more severe in patients with APS than in those without APS (median SDI score, 2 vs 0 at 5 years; P<.001; 4 vs 1 at 15 years; P<.001). Cumulative survival at 15 years was lower in patients with APS than in those without APS (65% vs 90%, P =.03). Older age at diagnosis, lupus nephritis, and APS were independent predictors of mortality. CONCLUSIONS: Antiphospholipid syndrome with thrombotic manifestations is a major predictor of irreversible organ damage and death in patients with SLE.