IgG immunoadsorption reduces systemic lupus erythematosus activity and proteinuria: a long term observational study.

OBJECTIVE: To analyse the effects of rigorous immunoglobulin removal by immunoadsorption (IAS) on proteinuria (primary outcome variable), disease activity (SIS, SLEDAI, ECLAM), and autoantibodies to double stranded DNA (anti-dsDNA) in active systemic lupus erythematosus (SLE). METHODS: 16 patients with severe SLE and renal disease, in whom cyclophosphamide was contraindicated or failed to halt disease progression, were treated with IAS for 3 months. Patients achieving at least 20% improvement in two or more of the outcome measures were considered responders and offered a 9 months' extension period. RESULTS: Within 3 months, 14 patients responded and 11 opted for an extension. Proteinuria decreased from 6.7 (4.6) g/day (mean (SD)) at baseline to 4.3 (3.5) g/day at 3 months and 2.9 (2.4) g/day at 12 months (p<0.001). From baseline to 3 and 12 months, disease activity improved independently of scoring by SIS (15 (5) to 5 (2) and to 5 (2), p<0.0001), SLEDAI (21 (7) to 5 (4) and to 5 (4), p<0.0001), or ECLAM (7 (2) to 2 (1) and to 3 (1), p<0.0001). Anti-dsDNA fell from 391 (647) IU/ml to 146 (218) and to 53 (50) IU/ml at 3 and 12 months, respectively. Steroids could be tapered from 117 (159) mg/day at baseline to 29 (17) mg/day at 3 months and 9 (2) mg/day at 12 months. IAS was not associated with an excess of infections. However, one patient died of septicaemia after 1 month of treatment. CONCLUSION: In this negatively selected cohort of patients with SLE, IAS was associated with a significant response shown by reduced proteinuria, improved global disease activity, decreased anti-dsDNA, and lower glucocorticoid dosages, suggesting therapeutic benefit.

The decanucleotide polymorphism in the factor VII promoter predicts factor VII plasma levels but not the risk of acute coronary syndromes.

It is known from large epidemiological studies that the elevation of coagulation factor VII in plasma is an independent risk factor for acute coronary syndromes. The level of factor VII is influenced by polymorphic sites in the factor VII gene. However, data on the association of such polymorphisms with the risk of acute coronary syndromes are conflicting. A decanucleotide insertion/deletion polymorphic site has been described in the promoter of the factor VII gene that leads to a dramatic change in the plasma factor VII levels. We therefore analyzed the association of this polymorphism with the risk of acute coronary syndromes in a case-control study. Included in the study were 111 patients with angiographically documented acute coronary syndromes and 108 age- and sex-matched individuals from the same geographic area without signs or symptoms of coronary heart disease. The presence or absence of the decanucleotide stretch at position -323 in the promoter of factor VII was monitored using a polymerase chain reaction (PCR)-based restriction technique. The prevalence of the genotype with the homozygous deletion was similar in the patients with acute coronary syndromes (79.2%) and in the control patients (79.6%). There was a non-significant trend toward a higher prevalence of the homozygote deletion in patients with premature acute coronary syndromes (77.4%) compared with an age-matched subgroup of the control patients (67. 5%) (odds ratio [OR] 1.6, confidence interval [CI] 0.95, 0.61-3.93). Thus, we could not find a significant association of the occurrence of acute coronary events with the insertion/deletion polymorphism in factor VII.

A prospective controlled trial comparing weekly self-testing and self-dosing with the standard management of patients on stable oral anticoagulation.

Oral anticoagulant therapy requires frequent laboratory controls of its intensity to assure therapeutic efficacy and to prevent potentially life threatening adverse events. It is generally assumed, that increasing the frequency of testing would lead to a better control of anticoagulation. We tested this hypothesis in a prospective controlled trial comparing weekly self-testing and self-dosing (self management) with the standard-management of these patients in an anticoagulation clinic. Only patients with stable anticoagulation were included into the study. We recorded 2733 weekly determinations of the intensity of anticoagulation (INR) in 49 patients on self-testing and self-dosing and 539 determinations of the INR in 53 patients on standard-management. Two intensities of anticoagulation were used in each group: a target INR of 3.5 for patients with artificial heart valves (target range: 2.5-4.5) and a target INR 2.5 (target range: 2.0-3.0) for patients with atrial fibrillation or venous thromboembolism. The deviation from the target INR, the fraction of INR determinations within the preset therapeutic range and the difference between the target INR and the actually achieved mean INR were the three major endpoints of the study. The mean deviation from the target INR was smaller in the groups of patients on self-management compared to the patients on standard-management. Individual deviations were significantly (p <0.0001) dependent on the type of management in interaction with the treatment intensity in a general linear model. Patients on weekly self-testing and self-dosing had more INR values within the therapeutic range than patients on standard-management (86.2% vs. 80.1% at INR range 2.5-4.5; 82.2 vs. 68.9 at INR range 2.0-3.0). The achieved mean INR was almost identical with the target INR in the patients on self-management but was significantly (p <0.005) below the target INR in the high intensity anticoagulation group on standard-management (target INR:3.5; achieved mean INR: 3.19; CI 0.95: 3.05-3.34). Our data show, that weekly self-testing and self-dosing leads to a better control of anticoagulation than standard treatment in an anticoagulation clinic.

The impact of Glu102Lys on the factor X function in a patient with a doubly homozygous factor X deficiency (Gla14Lys and Glu102Lys).

Two homozygous point mutations were found in a patient with factor X (FX) deficiency; One results in substitution of Lys for Gla+ 14 and the second causes a Lys substitution for Glu102. The proposita has a severely reduced FX coagulant activity in the extrinsic (<1% of normal) and in the intrinsic (30% of normal) system of coagulation and after activation with Russel's viper venom (18% of normal). The FX antigen is reduced in this patient to 20% of normal. The substitution of Lys for Glu102 in FX deficiency has been reported previously in a heterozygous state in conjunction with a Lys for Gla+14 substitution and with a Pro for Ser334 substitution. The contribution of the Lys for Glu102 substitution in the observed combined FX defect in these patients was unclear. The mutation causing the Glu102Lys substitution was introduced by site directed mutagenesis into a wild-type FX cDNA, and recombinant protein was expressed in HEK 293 cells. Compared to the wild-type FX cDNA, the mutant construct had a 67% activity upon activation in the extrinsic system, 93% activity upon activation in the intrinsic system and 72% after activation with RVV. The data presented show that the substitution of Lys for Glu102 results in a minor functional defect of the FX molecule.