Venous thromboembolism prevention in the acutely ill medical patient: a review of the literature and focus on special patient populations

Although venous thromboembolism (VTE) is a major public health problem, until recently, our understanding of the risk of VTE in hospitalized acutely ill medical patients has been incomplete. Fortunately, over the past 5 years, there has been an increasing body of literature that highlights the risk of VTE in the nonsurgical patient, identifies unique patient-risk factors, and defines adequate preventative measures. This review highlights the current literature with regard to epidemiology of VTE in hospitalized medical patients and the risk-stratification of these patients and deals with optimal preventative regimens and prevention strategies in special patient groups.     

Cardiac arrhythmias as the initial manifestation of adult primary Sjögren's syndrome: a case report and literature review

Two middle‐aged female patients presenting with heart palpitation and electrocardiogram revealed complex cardiac arrhythmias. A review of systems was positive for dry mouth and transient arthralgia, while laboratory and instrumental tests enabled us to make the diagnosis of primary Sjögren's syndrome (pSS). Cardiac electrophysiology revealed atrioventricular node dysfunction and impaired intraventricular conduction. Prednisone therapy induced a significant improvement in symptoms and electrocardiographic readings. The diagnosis of pSS should be considered in a patient presenting with complex cardiac arrhythmias.     

Presence of low levels of anti‐HBs antibody in so‐called ‘anti‐HBc alone’ subjects

Abstract: Background/Aims: The ‘anti‐Hbc alone’ pattern could sometimes be that of subjects who produced anti‐HBs after recovery, but at a lower level than that detectable using commercial assays. This study aimed to test this hypothesis. Methods: A total of 104 ‘anti‐HBc alone’ serum samples, i.e.positive for the anti‐HBc antibody but not for HBsAg nor for anti‐HBs antibody, were recruited when routine testing a broad population of employees, patients and pregnant women from a university hospital. A possible subliminal anti‐HBs production, that would have escaped detection by commercial EIAs, was investigated by comparing the optical densities (ODs) obtained in vaccinees (commercial anti‐HBs EIA) to those of a control group of 100 nonimmunised and nonvaccinated subjects. Results: The median OD was significantly higher (p<0.0001) in the ‘anti‐HBc alone’ subjects (OD=0.035) than in the controls (OD=0.023). Thirty‐six percent of the ‘anti‐HBc alone’ subjects had an anti‐HBs OD higher than the median OD of the controls+2SD. ‘Anti‐HBc alone’ subjects with anti‐HBe antibody had higher anti‐HBs ODs (0.041) than had those without anti‐HBe (0.029). In ‘anti‐HBc alone’ subjects, the anti‐HBs ODs, although under the cut‐off value of the EIA, were found to be higher than in the controls. Conclusion: Our results show low anti‐HBs production in some of the subjects studied.     

The evolution of T‐cell depletion in haploidentical stem‐cell transplantation

T‐cell depletion (TCD) can prevent the onset of graft‐versus‐host disease (GvHD) in animal models of bone marrow transplantation; this manipulation enabled the successful application in the 1980s of T‐cell depleted bone marrow (BM) for the treatment of babies with severe combined immune deficiency (SCID). However, in leukaemia patients, implementation of T‐cell depletion has been more difficult, especially due to high rate of graft‐rejection, leukaemia relapse and delayed immune reconstitution. These hurdles were gradually overcome by modifying the cell composition of the graft, and by reducing the toxicities associated with conditioning protocols. Although no ‘gold standard’ TCD method exists, T‐cell depletion in its modern forms could offer clinical benefit, even for patients with a matched sibling donor.     

Predictive and prognostic value of antinuclear antibodies and rheumatoid factor in primary Sjogren’s syndrome

Aims: To assess the predictive and prognostic value of antinuclear antibodies (ANA) and rheumatoid factor (RF) in primary Sjögren’s syndrome (pSS). Methods: This retrospective study includes 201 patients that fulfilled the 1993 European preliminary classification criteria for pSS. The patients were further categorized by the 2002 revised criteria, with or without the inclusion of ANA and RF as classification criteria, and were further subgrouped by the presence of ANA, RF, anti‐SS‐A, and anti‐SS‐B, and different ANA titers. The clinical manifestations, serological markers, and results of lip biopsies among these subgroups were compared. Results: Our results showed pSS patients who are seropositive for one of the following markers: ANA, RF, anti‐SS‐A, or anti‐SS‐B are younger, predominantly female, and had more serological abnormalities than those with seronegativity of ANA, RF, anti‐SS‐A, or anti‐SS‐B. Higher ANA titers (≥ 1 : 640) correlated with higher frequency of serum anti‐SS‐A+ and anti‐SS‐B+, and elevations of serum immunoglobulin G and A in all three different classification criteria groups. The clinical manifestations and laboratory results in the 2002 revised criteria groups with or without the inclusion of ANA and RF as classification criteria items were highly concordant. Conclusion: Regardless of the classification criteria for pSS, patients who are seropositive for one of the ANA, RF, anti‐SS‐A and anti‐SS‐B biomarkers are more likely to have autoimmune‐related Sjögren’s syndrome. ANA and RF have shown to possess the predictive and prognostic values for those who do not fulfill the higher stringent 2002 revised criteria but are indicated for immunomodulatory therapy. Thus we suggest that ANA and RF should be reconsidered as items of classification criteria for pSS.     

Therapy with biologic agents in SLE

The revolution of biologic targeted therapy for autoimmune disease is underway. While anticytokine treatment (anti‐TNF‐α and anti‐IL‐1Ra) are proving beneficial in such diseases as rheumatoid arthritis and spondyloarthropathies, the road to successful treatment in systemic lupus erythematosus (SLE) is more complex, and perhaps because the mechanisms of disease remain unelucidated. The aims of novel therapies in SLE are to target the autoimmune disease at different points: B‐cell depletion (Lymphostat‐B, Rituximab), inhibition of T–B interaction (IDEC‐131), blockade of cytokines (anti‐IL‐10 antibodies), manipulation of idiotypes (IVIG), tolerance induction to DNA and to Ig‐peptides and peptide therapy (Riquent). We review the current knowledge on biologic agents in SLE patients. We utililized MEDLINE for relevant information from 2000 to 2003. Since biologic agents in this disease are at preliminary stages, we include information from abstracts, open trials, as well as phase I, II, and III studies. Anecdotal reports are not included. B‐cell depletion therapy is promising.     

Diagnostic value of anti-modified citrullinated vimentin in rheumatoid arthritis

Background: Rheumatoid factors (RF) are currently used in the diagnosis of rheumatoid arthritis (RA). Several other autoantibodies found in RA are directed to epitopes in citrullinated proteins such as anti‐cyclic citrullinated and recently anti‐modified citrullinated vimentin (MCV). Objective: In this study we determined the sensitivity and specificity of anti‐MCV in comparison with anti‐cyclic citrullinated peptide (CCP) antibodies and RF in RA patients and in a control group using the American College of Rheumatology (ACR) criteria as the gold standard. Materials and methods: A cross sectional study was conducted from January to December 2008 on 100 patients with RA and 153 patients with arthritis or arthralgia but not fulfilling ACR criteria for RA. Serum from each subject was tested for anti‐MCV, anti‐CCP antibodies and immunoglobulin G (IgG) RF by enzyme‐linked immunosorbent assay. Sensitivity and specificity of the tests were evaluated using the ACR criteria as the gold standard. Results: The sensitivity of RF was 85% with 74.5% specificity. For anti‐CCP antibodies the sensitivity was 71% and the specificity was 94.8%. The sensitivity of anti‐MCV antibodies was 80% with 59.5% specificity. The area under the curve for RF was 0.759, for anti‐CCP antibodies was 0.866 and for anti‐MCV antibodies was 0.681, while for at least one positive test it was 0.691. Conclusion: Anti‐CCP antibodies have higher diagnostic specificity and positive predictive value than RF and anti‐MCV antibodies. RF has the highest sensitivity when compared to anti‐CCP and anti‐MCV antibodies. Thus anti‐MCV antibody is not a better marker when compared to RF or anti‐MCV antibody in the diagnosis of RA patients.     

The effect of rituximab on anti‐platelet autoantibody levels in patients with immune thrombocytopenia

Rituximab is an effective therapy resulting in a platelet count improvement in 60% of patients with immune thrombocytopenia (ITP). Rituximab depletes B cells; thus, a reduction in platelet autoantibody levels would be anticipated in patients who achieve a clinical response to this treatment. The objectives of this study were to determine whether rituximab was associated with a reduction in platelet autoantibody levels, and to correlate the loss of autoantibodies with the achievement of a treatment response. We performed a case‐control study nested within a previous randomized controlled trial of standard therapy plus adjuvant rituximab or placebo. We measured platelet‐bound anti‐glycoprotein (GP) IIbIIIa and anti‐GPIbIX using the antigen capture test. Of 55 evaluable patients, 25 (45%) had a detectable platelet autoantibody at baseline. Rituximab was associated with a significant reduction in anti‐GPIIbIIIa levels (P = 0·02) but not anti‐GPIbIX levels (P = 0·51) compared with placebo. Neither the presence of an autoantibody at baseline nor the loss of the autoantibody after treatment was associated with a response to rituximab. The subset of patients with persistent autoantibodies after treatment failed to achieve a platelet count response, suggesting that persistence of platelet autoantibodies can be a marker of disease severity.     

A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma

In this open‐label, multicentre, phase 1 study a fully human anti‐CD40 antagonist monoclonal antibody, lucatumumab, was evaluated in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to determine the maximum tolerated dose (MTD) based on dose‐limiting toxicities (DLTs). Secondary objectives included safety, pharmacokinetics, pharmacodynamics and antimyeloma activity. Twenty‐eight patients, enrolled using a standard ‘3 + 3’ dose escalation, received one or two (n = 3) cycles of lucatumumab 1·0, 3·0, 4·5 or 6·0 mg/kg once weekly for 4 weeks. Common lucatumumab‐related adverse events were reversible, mild‐to‐moderate infusion reactions. Severe adverse events were anaemia, chills, hypercalcaemia and pyrexia (7% each). DLTs included grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase and grade 4 increased lipase (n = 1 each). The MTD was 4·5 mg/kg. At doses ≥3·0 mg/kg, sustained receptor occupancy (≥87%), observed throughout weekly infusions up to 5 weeks after the last infusion, correlated with an estimated half‐life of 4–19 d. Twelve patients (43%) had stable disease, and one patient (4%) maintained a partial response for ≥8 months. These findings indicate that single‐agent lucatumumab was well tolerated up to 4·5 mg/kg with modest clinical activity in relapsed/refractory MM, warranting further study as a combination therapy.     

Autoimmune associated congenital heart block: integration of clinical and research clues in the management of the maternal / foetal dyad at risk

One of the strongest associations with autoantibodies directed to components of the SSA/Ro‐SSB/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. This risk is 10‐fold higher in women who have had a previously affected child with CHB. Anti‐Ro/La antibodies are necessary but insufficient to cause disease. In vitro and in vivo experiments suggest that the pathogenesis involves exaggerated apoptosis, macrophage/myfibroblast crosstalk, TGFβ expression and extensive fibrosis in the conducting system and in some cases surrounding myocardium. A disturbing observation is the rapidity of disease progression, with advanced heart block and life‐threatening cardiomyopathy observed <2 weeks from normal sinus rhythm. Once 3rd degree (complete) block is identified, reversal has never been achieved, despite dexamethasone. Current strategies include the evaluation of an early echocardiographic marker of injury, such as a prolonged PR interval and the use of IVIG as a preventative measure for pregnancies of mothers with previously affected children.     

A phase I study of a combination of anti-CD19 and anti-CD22 immunotoxins (Combotox) in adult patients with refractory B-lineage acute lymphoblastic leukaemia

Novel agents are needed for patients with refractory and relapsed acute lymphoblastic leukaemia (ALL). Combotox is a 1:1 mixture of two immunotoxins (ITs), prepared by coupling deglycosylated ricin A chain (dgRTA) to monoclonal antibodies directed against CD22 (RFB4‐dgRTA) and CD19 (HD37‐dgRTA). Pre‐clinical data demonstrated that Combotox was effective in killing both pre‐B‐ALL cell lines and cells from patients with pre‐B ALL. A clinical study of paediatric patients in which 3 of 17 patients with ALL experienced complete remission, supported the preclinical work and motivated this study. This study was a Phase I, dose‐escalation trial using Combotox in adults with refractory or relapsed B‐lineage‐ALL. A cycle consisted of three doses, with one dose given every other day. Dose levels were 3, 5, 6, 7 and 8 mg/m² per dose. Seventeen patients, aged 19–72 years, were enrolled in this multi‐institution study. The maximum tolerated dose was 7 mg/m²/dose (21 mg/m²/cycle) and vascular leak syndrome was the dose‐limiting toxicity. Two patients developed reversible grade 3 elevations in liver function tests. One patient achieved partial remission and proceeded to allogeneic stem cell transplantation. All patients with peripheral blasts experienced decreased blast counts following the administration of Combotox. Thus, Combotox can be safely administered to adults with refractory leukaemia.     

Characterization of hepatitis B virus surface antigen variability and impact on HBs antigen clearance under nucleos(t)ide analogue therapy

For hepatitis B virus (HBV)‐related chronic infection under treatment by nucleos(t)ide analogues (NUCs), HBsAg clearance is the ultimate therapeutic goal but very infrequent. We investigated how HBV envelope protein variability could lead to differential HBsAg clearance on NUCs. For 12 HBV genotype D patients receiving NUCs, six resolvers (HBsAg clearance) were compared to six matched nonresolvers (HBsAg persistence). PreS/S amino acid (aa) sequences were analysed with bioinformatics to predict HBV envelope antigenicity and aa covariance. To enrich our analyses on very rare resolvers, these were compared with other HBV genotype D strains in three characterized clinical cohorts including common chronically infected patients. The sT125M+sP127T combination was observed in four nonresolvers of six, corroborated by aa covariance analysis, associated with a lower predicted antigenicity than sT125T+sP127P. Concordant features within this HBV key functional domain, at positions 125 and 127, were reported from two of the three comparative cohorts. In our hands, a lower ELISA reactivity of HBV‐vaccinated mice sera was observed against the sT125M mutant. In the S gene, 56 aa changes in minor variants were detected in non‐resolvers, mainly in the major hydrophilic region, vs 28 aa changes in resolvers. Molecular features in patients showing HBsAg persistence on NUCs argue in favour of a different aa pattern in the HBV S gene compared to those showing HBsAg clearance. In nonresolvers, a decrease in HBs ‘a’ determinant antigenicity and more frequent mutations in the S gene suggest a role for the HBV envelope characteristics in HBsAg persistence.     

Anti‐citrullinated protein antibodies and their clinical utility in rheumatoid arthritis

One of the most important serological discoveries in rheumatology in recent years has been the characterization of autoantigens in rheumatoid arthritis (RA) containing the amino acid citrulline. There are many citrullinated proteins in the inflamed RA synovium. Rheumatoid factor (RF), which is the immunologic hallmark of RA, is not specific for RA, as it is found in 5% of healthy individuals and in 10–20% of those over the age of 65 years. RFs are of low titer in early disease stages when a clear diagnosis is often not yet possible; But anti‐citrullinated protein antibodies (ACPAs) can be found early in the disease course of RA, even years before the onset of clinical symptoms. The identification of citrullinated epitopes led to the development of the first and later second generation anti‐cyclic citrullinated peptide (anti‐CCP) antibody assays. Anti‐CCP2 antibody has shown a specificity of 98% in sera from patients with established RA and 96% in sera from subjects with early RA. Anti‐CCP can predict erosive disease, therefore could be a good serological marker for RA diagnosis.