Objective. In classic studies on the genetic background of antibody production, the major histocompatibility complex (MHC) has been shown to act as the most prominent immune response gene that controls the magnitude and the specificity of antibody production. The strongest genetic risk factor for rheumatoid arthritis (RA), the human MHC HLA-DRB1 shared epitope (SE) alleles, predisposes for antibodies against citrullinated proteins (ACPAs). ACPA levels are higher in SE-positive patients with RA than in SE-negative patients with RA. The aim of the present study was to determine whether SE influences not only the magnitude but also the specificity of the ACPA response.Methods. In 2 cohorts of anti-citrullinated peptide 2-positive patients with RA, one from a study of recent-onset arthritis (n ‫؍‬ 206) and the other from a treatment strategy study (n ‫؍‬ 141), serum antibodies against a citrullinated peptide derived from vimentin (cVim) and antibodies against a citrullinated fibrinogen peptide (cFibr) were determined by enzyme-linked immunosorbent assay. HLA-DRB1 genotyping was performed.Results. In the first cohort, SE alleles were significantly associated with the presence of antibodies against cVim (odds ratio [OR] 4.95, 95% confidence interval [95% CI] 1.87-15.3) and were not significantly associated with the presence of antibodies against cFibr (OR 1.71, 95% CI 0.70-4.14). These results were replicated in the second cohort (OR 5.05, 95% CI 1.92-13.6 and OR 1.19, 95% CI 0.30-3.97, respectively).Conclusion. In 2 cohorts of ACPA-positive patients with RA, SE alleles predisposed for the development of antibodies against cVim but not for the development of antibodies against cFibr. These data indicate that SE alleles act as "classic" immune response genes in the ACPA response, because they influence both the magnitude and the specificity of this RA-specific antibody response.

Acute renal failure (ARF) is one of the major complications after cardiopulmonary bypass for open heart operations. The present study was undertaken to identify the risk factors for the development of ARF following cardiopulmonary bypass (CPB). Four hundred and forty-seven consecutive patients who underwent open heart procedures from July 1994 to June 1995 were analyzed retrospectively. Their mean age was 55.6 +/- 14.2 (SD) years (range, 18 to 80). Dialysis was instituted whenever a patient exhibited inadequate urine output (<0.5 mL/kg/hr) for 2 to 3 hours despite correction of hemodynamic status and diuretic therapy, especially if fluid overload, hyperkalemia, or metabolic acidosis were also present. Twenty variables were analyzed by univariate analysis; these included nine preoperative variables--age, sex, hypertension, atherosclerosis, diabetes mellitus, left ventricular end-diastolic dimension (LVEDD) >5 cm, preoperative congestive heart failure, renal insufficiency (serum creatinine > or =130 micromol/L on two occasions), and sepsis--10 intraoperative variables--duration of CPB, redo procedures, emergency surgery, use of intraaortic balloon pump (IABP) in operating room, use of gentamicin, use of ceftriaxone, use of sulbactam/ampicillin, requirement of deep hypothermic circulatory arrest, duration of low mean perfusion pressure (mean pressure <50 mmHg for more than 30 minutes), operation on multiple valves--and one postoperative variable--significant hypotension (systolic blood pressure less than 90 mmHg for more than 1 hour). Significant variables or the variables having a trend (p<0.1) to be associated with ARF were included in stepwise multiple logistic regression analyses. Three regression analyses were performed separately. The incidence of ARF requiring dialysis in the study period was 15.0%. Significant risk factors for whole group of patients (regression I) were preoperative renal insufficiency (p<0.0001), postoperative hypotension (p<0.0001), cardiopulmonary bypass time more than 140 min (p<0.005), preoperative congestive heart failure (p<0.01), and history of diabetes mellitus (p<0.01). The risk factors in the valve group of patients (regression II) were preoperative renal insufficiency (p<0.0001) and postoperative hypotension (p<0.05). Risk factors in the CABG patients (regression III) were postoperative hypotension (p=0.0001), CPB time more than 140 min (p<0.05), preoperative renal insufficiency (p<0.05), and age (p<0.05). The authors conclude that preoperative renal insufficiency and postoperative hypotension are the most important independent risk factors for ARF in postcardiac surgical patients. In addition, CPB time greater than 140 minutes and old age are also independent risk factors for ARF in CABG patients. CPB time more than 140 minutes, history of diabetes mellitus, and preoperative congestive heart failure are independent risk factors for development of ARF in our total group of patients. These findings may have important clinical implications in the prevention of ARF in postcardiac su...

Background: Antibodies directed against citrullinated proteins (eg anti-cyclic citrullinated peptide (CCP)) have excellent diagnostic and good prognostic potential for rheumatoid arthritis. Type 1 autoimmune hepatitis (AIH-1) is a chronic liver disease characterised by a variety of serum autoantibodies. Recently, in a large group of patients with AIH-1 without clear rheumatoid arthritis overlap, a relatively high percentage (9%) of anti-CCP2 positivity was scored. Objectives: To characterise the citrulline-dependence of the observed anti-CCP2 positivity in AIH-1 sera as well as in other groups of patients without rheumatoid arthritis (mainly rheumatic diseases). Methods: Serum samples of 57 patients with AIH-1 and 66 patients without rheumatoid arthritis, most of them reported as anti-CCP positive, were tested for citrulline-specific reactivity with a second generation anti-CCP kit, with the citrullinated and the corresponding non-citrullinated (arginine-containing) antigen. A subset of AIH-1 sera was also tested with a CCP1 ELISA (and arginine control). Results: The anti-CCP2 reactivity of most non-rheumatoid arthritis rheumatic diseases samples (87-93%) was citrulline-specific, whereas a relatively high percentage of AIH-1 samples (42-50%) turned out to be reactive in a citrulline-independent manner. The use of citrullinated and non-citrullinated CCP1 peptides confirmed a high occurrence of citrulline-independent reactivity in AIH-1 samples. Conclusions: In rheumatoid arthritis and most non-rheumatoid arthritis rheumatologic disease sera, anti-CCP positivity is citrulline-dependent. However in some patients, particularly patients with AIH-1, citrullineindependent reactivity in the anti-CCP2 test can occur. A positive CCP test in a non-rheumatic disease (eg liver disease) should therefore be interpreted with care, and preferably followed by a control ELISA with a noncitrullinated antigen.

In a prospective, randomized, parallel study, two regimens of platelet-suppressant therapy (PST) dipyridamole-aspirin and pentoxifylline-aspirin were compared with standard oral anticoagulation with warfarin in the prevention of prosthetic heart valve thromboembolism. In the entire group of 254 patients followed for 395.6 patient-years, the thromboembolic rate was significantly less in the warfarin group (warfarin vs dipyridamole-aspirin, p < .005; warfarin vs pentoxifyllineaspirin, p < .05). Subgroup analysis disclosed that, in patients with isolated mitral valve replacement, warfarin was superior to both of the PSTs with respect to the prevention of thromboembolism (warfarin vs dipyridamole-aspirin, p = .005; warfarin vs pentoxifylline-aspirin, p < .05). Furthermore, a significant number of our patients could not tolerate the antiplatelet agents. However, in the rare situation in which repeated significant bleeding occurs despite careful adjustment of the dosage of warfarin, PST may be an acceptable alternate method of thromboembolism prophylaxis. Circulation 72, No. 5, 1059No. 5, -1063No. 5, , 1985. WHEN THE EFFECT of anticoagulant is maintained within a therapeutic range it significantly reduces, but does not eliminate, the risk of thromboembolism in patients with prosthetic heart valves. ' However, adequate anticoagulation at all times is difficult to achieve,2 and it carries a definite risk of its own.3 In clinical practice, whenever the use of oral anticoagulation is complicated, e.g., in children with prosthetic heart valves or when adequate facilities for careful anticoagulation are not available, antiplatelet agents have been used as the alternatives.4 It would be advantageous to patients with prosthetic heart valves if platelet-suppressant therapy (PST) could be used in place of oral anticoagulation. We undertook a prospective, randomized, parallel study to evaluate the efficacy of PST for the prevention of thromboembolism in patients with mechanical prosthetic heart valves. AntiFrom the

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