Actin-free Gc globulin: a rapidly assessed biomarker of organ dysfunction in acute liver failure and cirrhosis.

Reductions in serum levels of Gc globulin, a hepatically synthesized component of the extracellular actin scavenger system responsible for complexing circulating actin and attenuating intravascular microthrombus formation, are associated with poor outcome in acute liver failure. Clinically applicable assays of the important actin-free fraction (Af-Gc) have not been available until now. We measured actin-free Gc globulin levels with a novel, rapid assay in 61 cases of acute liver failure (ALF) and in 91 patients with cirrhosis (40 of whom were clinically unstable with extrahepatic organ dysfunction), and studied associations with liver dysfunction, extrahepatic organ dysfunction, indices of disseminated coagulation, and outcome. Reductions in Af-Gc levels mirrored hepatic dysfunction and organ dysfunction in both groups, and discriminated patients with poor prognosis from those with good prognosis in the ALF cohort. Levels were lowest in patients with ALF (10% of control values), but levels were also markedly reduced in both unstable (28%) and stable (44%) patients with cirrhosis. Associations with markers of disseminated intravascular coagulation were seen in both groups, most notably in the cirrhosis cohort, supporting a pathophysiological role for reduced Af-Gc in the evolution of organ dysfunction. In acetaminophen-induced ALF, Af-Gc identified patients with poor prognosis as well as did the Acute Physiology and Chronic Health Evaluation (APACHE II) score (area under the receiver operating characteristic curve, 0.7), and in cirrhosis, Af-Gc was an independent predictor of mortality by multifactorial analysis. In conclusion, the importance of Af-Gc reductions in the development of multiple organ dysfunction in ALF and cirrhosis is highlighted, probably resulting from reduced hepatic production and peripheral exhaustion of this arm of the extracellular actin scavenger system.     

Neonatal Liver Disease Associated with Placental Transfer of Anti-mitochondrial Antibodies

Background: Anti-mitochondrial antibody is the diagnostic hallmark of primary biliary cirrhosis. Its role in the aetiology of primary biliary cirrhosis is controversial. Methods: Two cases of neonatal hepatitis seropositive for anti-mitochondrial antibody are described. Anti-mitochondrial antibody Ig isotype and epitopic specificity were investigated by immunofluorescence and enzyme immunoassays. Results: In both infants anti-mitochondrial antibody was of the G class, mainly G1 and G3 subclasses, and reacted with two synthetic peptides reproducing major M2 epitopic regions: inner lipoyl domain pyruvate dehydrogenase complex (PDC)-E2_162-176 and PDC-E3 binding protein (PDC-E3BP)_86-100. One infant also reacted with outer lipoyl domain PDC-E2_35-49, and 2-oxoglutarate dehydrogenase complex (OGDC)-E2_99-113. An identical pattern of reactivity was present in their mothers, indicating the maternal origin of the antibodies. Anti-mitochondrial antibody disappeared in the infants with the disappearance of the liver pathology. Conclusions: The simultaneous disappearance of hepatitis and anti-mitochondrial antibody in the infants suggests a possible causal link between the two.     

Testing of a New T‐Wave Subtraction Algorithm as an Aid to Localizing Ectopic Atrial Beats

Background: Identifying the timing and morphology of an ectopic P wave from the surface electrogram can aid in the diagnosis and localization of atrial arrhythmias. Given the relatively short coupling interval of atrial ectopic beats, the P wave is often obscured by the larger amplitude QRS‐T wave complex. A method to uncover such “buried” P waves using a standard 12‐lead surface ECG would be clinically useful and could potentially be a noninvasive guide to catheter ablation of focal atrial tachycardia. Methods: We developed an automated computerized program (BARD DUO LAB SYSTEM?) designed to subtract the QRS‐T wave complex from the surface electrogram and uncover a previously obscured P wave. The purpose of the present study was to validate this program. The surface ECG from 21 patients undergoing atrial pacing during electrophysiologic study (group I) and 10 patients with atrial tachycardia (group II) were analyzed and the derived P‐wave morphology assessed using correlation waveform analysis (CWA) and visual grading by three reviewers. Results: The algorithm successfully uncovered the P wave in each surface ECG. For the 21 patients in group I, average CWA comparing the derived P wave with the previous paced P wave was 83%. Average CWA for group II was 82%. Visual grading of the match between derived P waves and paced P waves revealed a 21/21 match in group I patients and a 12/12 match in 9/10 of group II patients. Conclusions: An ectopic atrial P wave obscured by a coincident QRS‐T wave complex can be accurately uncovered using this new algorithm. Addition of this technique to existing methods may improve the diagnosis of atrial arrhythmias and aid in the localization and ablation of ectopic atrial foci.     

Diagnosis of antiphospholipid syndrome

Antiphospholipid syndrome is a multisystem autoimmune disease, characterized by recurrent vascular thrombosis and/or pregnancy losses in the presence of persistently positive antiphospholipid antibodies. In clinical practice, testing for anticardiolipin antibodies and lupus anticoagulant is mandatory for the laboratory diagnosis of antiphospholipid syndrome. Identification of patients with antiphospholipid syndrome is important, as prophylactic anticoagulant therapy may prevent thrombosis from recurring, and treatment during pregnancy can improve fetal and maternal outcome.     

Extraction of Buried P Waves from Printed Electrocardiograms

Background: Morphologic identification of ectopic P‐waves from surface ECGs can be challenging, particularly when the P‐wave is buried in the QRST wave complex. Because ECGs are often available on paper and not digitally, we developed a method of subtracting the T‐wave from the buried P‐wave complex on paper ECGs. Methods: To validate our system, an atrial extrastimulus was introduced during and following the T‐wave. The ECGs were scanned and then transformed from an image format to a digital format. A computer algorithm digitally subtracted a QRST with no buried P‐wave from one with a buried P‐wave, thus resulting in an extracted P‐wave. The extracted P‐waves were compared to the nonburied P‐wave by determining correlation coefficients and by visual grading by two independent reviewers. Results: Visual grading comparing the buried P‐wave with the exposed paced P‐wave was 94%. The median correlation coefficient was 85%. Conclusions: An ectopic atrial P‐wave obscured by a coincident QRST wave complex can be accurately derived from printed ECG using this PC‐based system. Addition of this technique to the existing methods may aid in the localization and ablation of ectopic atrial foci.     

Thalidomide for the treatment of resistant cutaneous lupus: efficacy and safety of different therapeutic regimens

PURPOSE: Thalidomide is effective for the treatment of severe cutaneous lupus. Our aim was to study the safety and efficacy of different doses of thalidomide in this condition. METHODS: We studied patients with severe cutaneous lupus that was unresponsive to antimalarials, prednisolone, methotrexate, azathioprine, and cyclosporin A. Starting doses of 100 mg daily (n = 16 patients), 50 mg daily (n = 17), or 50 mg on alternate days (n = 15) were compared. The response to thalidomide was categorized as complete remission, partial remission, or no visible improvement. All patients received a baseline electromyogram (EMG) followed by repeat EMG every 3 to 6 months, or sooner if neuropathic symptoms developed. RESULTS: Forty-eight patients (46 female; mean [+/- SD] age, 44 +/- 12 years; range, 22 to 71 years) with discoid lupus (n = 18), subacute cutaneous lupus (n = 6), or systemic lupus erythematosus with skin involvement (n = 24) were included. The response rate was 81%, including 29 patients (60%) in complete remission and 10 (21%) in partial remission. Nine patients (19%) failed to respond. Thirteen patients (27%) developed peripheral neuropathy, which was EMG-proven in 11, including 4 patients in the 50-mg alternate-day group. Other side effects included drowsiness, constipation or abdominal pain, and amenorrhea. The relapse rate after stopping thalidomide was 67% (26/39). There was no association between a positive response to the drug and either starting doses or cumulative dose. Similarly, no association was found between peripheral neuropathy and the starting or cumulative dose. CONCLUSION: Thalidomide is effective for the treatment of severe cutaneous lupus. There were no clear dose-dependent effects. However, the high incidence of neurotoxicity, even at low doses, suggests that it may be most useful as a remission-inducing drug.     

Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5

BACKGROUND: Prolonged anticoagulation is the treatment of choice for patients with thrombosis and the antiphospholipid syndrome. However, there is still debate about the optimum intensity of anticoagulation. METHODS: The study included 66 patients with antiphospholipid syndrome (Sapporo criteria) and previous thrombosis. All were receiving oral anticoagulation to a target international normalized ratio of 3.5. Every patient was individually interviewed to recall major bleeding and thrombotic episodes during the previous 12 months. RESULTS: Patients were mainly women and white. The rate of major bleeding was 6 cases per 100 patient-years (95% confidence interval [CI] 1.6-15.0). The rate of intracranial bleed was 1.5 per 100 patient-years (95% CI, 0.04-8.4). None of the bleeding episodes was fatal. The rate of thrombotic recurrences was 9.1 cases per 100 patient-years (95% CI, 3.3-19.6). Most recurrences took place in the same vascular bed as the original thrombosis. Age, time receiving anticoagulant therapy, primary vs secondary antiphospholipid syndrome, positivity for anticardiolipin antibodies, positivity for lupus anticoagulant, previous arterial thrombosis, previous stroke, previous venous thrombosis, and previous thrombocytopenia were not predictive of bleeding events. However, the risk of thrombotic recurrences was independently higher in patients who were receiving anticoagulation for longer periods. CONCLUSIONS: The risk of intracranial and fatal bleeding in patients with definite antiphospholipid syndrome and previous thrombosis treated with oral anticoagulation to a target international normalized ratio of 3.5 is similar than in groups of patients treated to lower target ratios. The risk of thrombotic recurrences, even during anticoagulation, was high. Most recurrences took place in the same territory as original thromboses.     

B-cell-depleting therapy in systemic lupus erythematosus

The emergence of a new class of agents (B-cell-depleting therapies) has opened a new era in the therapeutic approach to systemic lupus erythematosus, with belimumab being the first drug licensed for use in systemic lupus erythematosus in more than 50 years. Four agents deserve specific mention: rituximab, ocrelizumab, epratuzumab, and belimumab. Controlled trials have shown negative results for rituximab, promising results for epratuzumab, and positive results for belimumab. Despite these negative results, rituximab is the most-used agent in patients who do not respond or are intolerant to standard therapy and those with life-threatening presentations. B-cell-depleting agents should not be used in patients with mild disease and should be tailored according to individual patient characteristics, including ethnicity, organ involvement, and the immunological profile. Forthcoming studies of B-cell-directed strategies, particularly data from investigations of off-label rituximab use and postmarketing studies of belimumab, will provide new insights into the utility of these treatments in the routine management of patients with systemic lupus erythematosus.     

Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q(10) treatment

The exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q(10) (CoQ(10)). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors. Increased peroxide production, nuclear abundance of Nrf2, antioxidant enzymatic activity, decreased intracellular glutathione, and altered mitochondrial membrane potential were found in monocytes and neutrophils from APS patients. Accelerated atherosclerosis in APS patients was found associated with their inflammatory or oxidative status. CoQ(10) preincubation of healthy monocytes before IgG-antiphospholipid antibody treatment decreased oxidative stress, the percentage of cells with altered mitochondrial membrane potential, and the induced expression of tissue factor, VEGF, and Flt1. In addition, CoQ(10) significantly improved the ultrastructural preservation of mitochondria and prevented IgG-APS-induced fission mediated by Drp-1 and Fis-1 proteins. In conclusion, the oxidative perturbation in APS patient leukocytes, which is directly related to an inflammatory and pro-atherothrombotic status, relies on alterations in mitochondrial dynamics and metabolism that may be prevented, reverted, or both by treatment with CoQ(10).     

Is it time for biosimilars in autoimmune diseases?

The last two decades have witnessed a revolution in the treatment of autoimmune diseases due to the introduction of biological agents which, although now included as standard treatment in patients with autoimmune rheumatological, dermatological and gastrointestinal diseases. The use of biological agents is associated with greater costs compared with the mainly anti-inflammatory and immunosuppressant drugs used in the pre-biological era. Biosimilars are highly similar copies of biological drugs, but not identical to approved ‘reference’ agents. Biological agents are complex proteins involved in the immune response and their exact replicas are extremely difficult, if not impossible, to obtain. Three scenarios have converged to provide a specific opportunity for biosimilars in autoimmune diseases: growing demand for biologics due to successful clinical use; the nearing of patent expiry for the four top-selling biological brands; and the search to reduce health costs due to the financial crisis. We aimed to review the crucial topics of efficacy, safety and regulatory approach of upcoming biosimilars.