Tuberculosis and granuloma formation in patients receiving anti-TNF therapy.

In patients receiving anti-tumor necrosis factor (TNF) therapy, a probable exacerbation of latent tuberculosis (TB) is a major adverse event. The impairment of granuloma differentiation is considered a characteristic feature of TB in these patients. In this report we present three patients with rheumatic disease who developed TB under infliximab treatment. All of them had typical granulomas on the biopsy specimens, indicating that the expected impairment of granuloma formation is not always the case. The notion of granuloma-free TB in patients receiving anti-TNF therapy could shift a clinician's path away from performing a biopsy, thus delaying the establishment of a correct diagnosis.     

Levels of soluble CD40 ligand (CD154) in serum are increased in human immunodeficiency virus type 1-infected patients and correlate with CD4(+) T-cell counts

CD40 ligand (CD40L or CD154) is a costimulatory molecule expressed mainly on activated CD4(+) T cells. Concentrations of the soluble form of CD40L (sCD40L) in serum were determined for a cohort of 77 human immunodeficiency virus type 1 (HIV-1)-infected patients before and after initiation of highly active antiretroviral treatment (HAART) by a quantitative enzyme-linked immunosorbent assay. Circulating sCD40L levels were higher by twofold in untreated patients than in healthy controls (means +/- standard deviations [SD]: 1.41 +/- 1.48 versus 0.69 +/- 0.59 ng/ml; P < 0.001). HIV-1-infected patients classified as CD4 T-cell category 1 had significantly higher sCD40L levels than patients classified as CD4 categories 2 and 3 (mean +/- SD: 2.08 +/- 1.46 ng/ml versus 1.57 +/- 1.58 [category 2] and 0.94 +/- 1.25 ng/ml [category 3]; P = 0.046), while no correlation with clinical categories A, B, and C was found. Individual serum sCD40L levels correlated with CD4(+) T-cell counts (P = 0.039) but not with viral load, gamma globulin levels, or acute-inflammatory-response markers. After 8 to 12 months of HAART, a further threefold increase of serum sCD40L levels, which paralleled the increase of CD4(+) T-cell counts, was observed. These novel findings suggest that sCD40L measurement in HIV-1-infected patients could serve as a new surrogate marker useful in the assessment of treatment efficacy, especially in settings where well-equipped laboratories and funding required for CD4(+) T-cell count and viral load measurements are not available.     

Gene-specific formation and repair of DNA monoadducts and interstrand cross-links after therapeutic exposure to nitrogen mustards.

PURPOSE: To investigate the possibility of measuring the gene-specific DNA damage after therapeutic exposure to nitrogen mustards and to examine its relationship with the clinical response. EXPERIMENTAL DESIGN: The kinetics of gene-specific monoadducts and interstrand cross-link formation/repair were measured in the p53 and N-ras genes. DNA extracted from human peripheral lymphocytes following in vitro exposure to melphalan or therapeutic exposure to melphalan or cyclophosphamide was used. RESULTS: When lymphocytes were treated in vitro with biologically relevant doses of melphalan, monoadducts accumulated rapidly in both p53 and N-ras genes, reaching maximal levels within 2 h, whereas the highest interstrand cross-link levels were found within 8 h. Thereafter, the adducts were repaired with half-lives of 14.5 +/- 0.3 h (p53) or 18.8 +/- 1.5 h (N-ras) for monoadducts and 12.4 +/- 0.8 h (p53) or 14.1 +/- 2.2 h (N-ras) for interstrand cross-links. Moreover, peak levels of monoadducts in both genes were observed 2 h after treatment in peripheral leukocytes from patients with multiple myeloma treated with high-dose i.v. melphalan, supported by autologous stem cell transplantation, whereas interstrand cross-links were maximal within 8 h. Of seven patients examined, the three who showed the least levels of DNA damage did not respond to the high-dose melphalan. CONCLUSIONS: This is the first report showing that it is feasible to measure gene-specific DNA damage in a readily accessible tissue of humans exposed to bifunctional alkylating drugs and to examine, at the level of the individual patient, the relationships between the induction/repair of cytotoxic DNA damage and clinical response or long-term complications.     

Extent of damage and repair in the p53 tumor-suppressor gene after treatment of myeloma patients with high-dose melphalan and autologous blood stem-cell transplantation is individualized and may predict clinical outcome.

PURPOSE: To quantitate the individual levels of melphalan-induced DNA damage formation and repair in vivo and to search for possible correlations with clinical outcome in patients with multiple myeloma (MM). PATIENTS AND METHODS: The formation and subsequent repair of DNA damage (monoadducts and interstrand cross-links) in the p53 tumor-suppressor gene, the proto-oncogene N-ras, and the housekeeping gene beta-actin during the first 24 hours after treatment with high-dose melphalan (HDM; 200 mg/m2) supported by autologous blood stem-cell transplantation (ABSCT) was measured in blood leukocytes of 26 patients with MM. The peak DNA adduct levels, the total amount of adducts over time, and the rate of adducts repair in each gene were correlated with response and time to progression after HDM. RESULTS: The levels of gene-specific DNA damage formation and the individual repairing capacity varied up to 16-fold among patients, indicating that the melphalan-induced biologic effect in vivo is highly individualized. A significantly greater DNA damage and a slower rate of repair in p53 for all end points under study were found in patients who achieved tumor reduction compared with nonresponding patients. Furthermore, longer progression-free survival correlated with increased peak monoadduct levels in the p53 gene (P = .032). CONCLUSION: Increased DNA damage and slower repairing capacity in the p53 gene from blood leukocytes after HDM correlate with improved outcome of patients with MM who undergo ABSCT. These results suggest that quantitation of such biologic end points may identify patients who are more likely to benefit from this procedure.     

Impact of non-steroidal anti-inflammatory drugs on cardiovascular risk: Is it the same in osteoarthritis and rheumatoid arthritis?

Although large-scale population studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of myocardial infarction, this is not confirmed in patients with rheumatoid arthritis (RA). Herein, we review the litterature on the differential effects of NSAIDs on cardiovascular risk in osteoarthritis (OA) versus RA and discuss possible explanations for this discrepancy. To assess a potential additive effect of age in non-RA populations, we compared weighted mean age between RA patients and unselected NSAID users included in cohort and case–control studies that estimate the cardiovascular risk of NSAIDs, assuming that the main indication for NSAID usage in elderly populations is OA. Our hypothesis that advanced age in osteoarthtitis compared to RA patients confounds the effect of NSAIDs on cardiovasular risk was not confirmed. Several other hypotheses that can be proposed to explain this counterintuitive effect of NSAIDs on the cardiovascular risk of RA patients are discussed. We conclude that patients with RA have a lower cardiovascular disease risk associated with the use of NSAIDs, probably due to the nature of their disease per se, until further research indicates differently.     

A Review on Joint Carotid Intima-Media Thickness and Plaque Area Measurement in Ultrasound for Cardiovascular/Stroke Risk Monitoring: Artificial Intelligence Framework

Journal of Digital Imaging - Cardiovascular diseases (CVDs) are the top ten leading causes of death worldwide. Atherosclerosis disease in the arteries is the main cause of the CVD, leading to...     

Can premenstrual syndrome affect arterial stiffness or blood pressure?

ObjectiveWe tested the hypotheses that monthly fluctuations in markers of arterial stiffness and blood pressure hemodynamics differ between women with and without premenstrual syndrome. We also assessed hypertension prevalence and arterial stiffening in postmenopausal women with or without history of premenstrual symptoms.MethodsTwenty one pre-menopausal women with premenstrual syndrome and 15 women without were prospectively examined in three distinct phases of their menstrual cycle (menses, late follicular and luteal phase). Pulse-wave velocity and analysis were used to assess arterial stiffness and wave reflection indices, respectively. Endothelial function was evaluated by flow-mediated vasodilation. In a cross-sectional substudy, 156 postmenopausal women were assessed for possible associations between retrospectively reported PMS symptoms and hypertension.ResultsIn women with premenstrual syndrome, arterial stiffness significantly increased during the luteal and menses phase (late follicular: 6.48 ± 1.07, luteal: 7.1 ± 1.26, menstruation: 7.12 ± 1.19 m/s, p = 0.003), while blood pressure peaked at the menses phase. Significant interactions between PMS and changes in arterial stiffness and blood pressure but not endothelial function, were observed. Changes in PWV were significantly associated with concomitant changes in blood pressure, C-reactive protein and the severity of PMS symptoms. The prevalence of hypertension (20.9% vs. 40.9%, p = 0.041) and pulse-wave velocity values (8.64 ± 1.52 vs. 9.37 ± 1.1, p = 0.046) were higher in postmenopausal women with 7 or more reported PMS symptoms. Arterial stiffness differences remained significant after adjustment for confounding factors.ConclusionThese results imply that PMS may affect arterial stiffness and BP monthly variability. Whether PMS is associated with new onset hypertension later in life needs further evaluation.     

Rituximab anti-B-cell therapy in systemic lupus erythematosus: pointing to the future

PURPOSE OF REVIEW: To discuss the clinical effects and the immunologic consequences of transient B-cell depletion using the anti-CD20 monoclonal antibody rituximab in systemic lupus erythematosus. RECENT FINDINGS: A total of 100 rituximab-treated patients with severe disease, refractory to major immunosuppressive treatment, have been reported so far. Within a median follow-up period of 12 months rituximab was well tolerated, which is compatible with the experience accumulated from its use in more than 500 000 lymphoma patients. About 80% of patients achieved marked and rapid reductions in global disease activity. Because of the clinical heterogeneity, dosing differences, and concomitant treatments, including cyclophosphamide in 35% of patients, a proper evaluation of the clinical efficacy or rituximab is difficult. Variable degrees of clinical benefit have been reported for all clinical systemic lupus erythematosus manifestations, including active proliferative nephritis. Whereas 4-weekly infusions of 375 mg/m of rituximab result in complete B-cell depletion lasting most often from 3 to 8 months, a prolonged depletion does not always correlate with a more favorable clinical response. Total immunoglobulin levels and protective antibodies are preserved, but anti-dsDNA antibody titers decrease, often independently of the clinical response. SUMMARY: The findings reviewed point to a growing optimism for targeting B cells in the treatment of systemic lupus erythematosus; therefore double-blind studies comparing rituximab with existing immunosuppressive therapies are needed. Moreover, careful assessments of the effects of transient B-cell depletion on distinct autoimmune pathogenetic processes will enable optimization of therapeutic single or combined therapeutic schemes.     

Diagnosis and management of Neuro-Behçet’s disease: international consensus recommendations

Neuro-Behçet’s disease (NBD) is one of the more serious manifestations of Behçet’s disease (BD), which is a relapsing inflammatory multisystem disease with an interesting epidemiology. Though NBD is relatively uncommon, being potentially treatable, neurologists need to consider it in the differential diagnosis of inflammatory, infective, or demyelinating CNS disorders. Evidence-based information on key issues of NBD diagnosis and management is scarce, and planning for such studies is challenging. We therefore initiated this project to develop expert consensus recommendations that might be helpful to neurologists and other clinicians, created through an extensive literature review and wide consultations with an international advisory panel, followed by a Delphi exercise. We agreed on consensus criteria for the diagnosis of NBD with two levels of certainty in addition to recommendations on when to consider NBD in a neurological patient, and on the use of various paraclinical tests. The management recommendations included treatment of the parenchymal NBD and cerebral venous thrombosis, the use of disease modifying therapies, prognostic factors, outcome measures, and headache in BD. Future studies are needed to validate the proposed criteria and provide evidence-based treatments.