False-positive Test For Syphilis Research Articles

Clinical Evaluation of Fully Automated Elecsys® Syphilis Assay for the Detection of Antibodies of Treponema pallidum.

The resurgence of syphilis in recent years has become a serious threat to the public health worldwide, and the serological detection of specific antibodies against Treponema pallidum (TP) remains the most reliable method for laboratory diagnosis of syphilis. The performance of the Elecsys® Syphilis assay, a brand new electrochemiluminescene immunoassay (ECLIA), was assessed by large amounts of samples in this study. In comparison with InTec assay, the Elecsys® Syphilis assay was evaluated in 146 preselected samples from patients with syphilis, 1803 clinical routine samples, and 175 preselected samples from specific populations with reportedly increased rates of false-positive syphilis test results. Discrepancy samples must be investigated by Mikrogen Syphilis recomline assay. There was an overall agreement of 99.58% between two assays (Kappa = 0.975). The sensitivity and specificity of the Elecsys® Syphilis assay were 100.0% (95% CI, 96.8-100.0%) and 99.8% (95% CI, 99.5-100.0%), respectively. The Elecsys syphilis assay displays better sensitivity (100%), specificity (99.8%), PPV (98.7%), and NPV (100%) in 2124 samples enrolled, compared with the InTec assay. Considering the excellent ease of use and automation, high throughput, and its superior sensitivity, especially in primary syphilis, the Elecsys® Syphilis assay could represent an outstanding choice for screening of syphilis in high-volume laboratories. However, more attention was still needed, or the results must be confirmed by other treponemal immunoassays. The new Elecsys® Syphilis assay is applied to patients with malignant neoplasm or HIV infection.

Antiphospholipid syndrome: Laboratory testing and diagnostic strategies

The antiphospholipid syndrome (APS) is diagnosed in patients with recurrent thromboembolic events and/or pregnancy loss in the presence of persistent laboratory evidence for antiphospholipid antibodies. Diagnostic tests for the detection of antiphospholipid antibodies include laboratory assays that detect anticardiolipin antibodies, lupus anticoagulants, and anti-β(2)-glycoprotein I antibodies. These assays have their origins beginning >60 years ago, with the identification of the biologic false positive test for syphilis, the observation of "circulating anticoagulants" in certain patients with systemic lupus erythematosus, the identification of cardiolipin as a key component in the serologic test for syphilis, and the recognition and characterization of a "cofactor" for antibody binding to phospholipids. Although these assays have been used clinically for many years, there are still problems with the accurate diagnosis of patients with this syndrome. For example, lupus anticoagulant testing can be difficult to interpret in patients receiving anticoagulant therapy, but most patients with a thromboembolic event will already be anticoagulated before the decision to perform the tests has been made. In addition to understanding limitations of the assays, clinicians also need to be aware of which patients should be tested and not obtain testing on patients unlikely to have APS. New tests and diagnostic strategies are in various stages of development and should help improve our ability to accurately diagnose this important clinical disorder.

Hepatitis C virus infection and biological falsepositive syphilis test: a single-center experience

Rapid plasma regain positive and/or treponema pallidum hemagglutination negative [RPR(+)/TPHA(-)] results were designated as biologic false-positive (BFP). There are limited data about BFP reactions against syphilis in patients with hepatitis C virus (HCV) infection. This study aimed to determine the prevalence of BFP reactions for syphilis in patients with HCV infection in a large sample and assess the relationship between BFP reactions and HCV infection. A total of 2656 patients with positive anti-HCV and 5600 healthy control subjects were enrolled in this study. Hepatitis C serology was determined by a second generation ELISA test for HCV antibody. Syphilis serology was determined by the RPR test. Those subjects with reactive RPR positive underwent the TPHA test. Demographics and laboratory data were collected by trained clinicians. Among 2656 patients, 111 (4.2%) had a reactive RPR test. Of the 111 patients who were subjected to reactive RPR test, 30 (27.0%) showed HCV(+)/RPR(+). Of 5600 healthy controls, 80 (1.4%) had a reactive RPR test. Fourteen (17.5%) controls with HCV(-)/RPR(+) had a non-reactive TPHA test. These represented 1.1% of all HCV-positive and 0.3% of all HCV-negative subjects (P<0.001). A significantly increased prevalence shown by false-positive tests for syphilis was observed in elderly HCV-seropositive patients. BFP-HCV positive group had a higher prevalence of eosinophilia. The eosinophil abnormality was compared between the patients and controls (66.7% vs 21.4%, P=0.0043). No significant results were observed in antinuclear antibodies, antiphospholipid and complement (C3, C4) (P>0.05). The data of this study demonstrate that HCV infection is associated with a false-positive RPR test. In this study BFPs were significantly more common in HCV positive patients compared to HCV-negative ones. Eosinophil abnormality can be considered as a predictor for BFP. Excessive BFPs must be considered in assessing the frequency of syphilis in a HCV-positive population and the importance of the treponemal specific serologic test should be emphasized for a diagnosis of syphilis in such population.

False positive reactions in confirmatory tests for syphilis in presence of antiphospholipid antibodies: misdiagnosis with prognostic and social consequences

False-positive reactions in the Venereal Disease Research Laboratory test are well known, whereas a positive fluorescent treponemal antibody absorption assay is rarely thought to be a false positive. The non-recognition of serological false-positive tests for syphilis may have negative prognostic and social implications.

Factor V Leiden mutation in Sneddon syndrome

Sneddon syndrome (SNS) is characterized by the association of ischaemic cerebrovascular events and widespread livedo racemosa. Its pathophysiology is still controversial. The aim of this study was to evaluate the prevalence of factor V Leiden mutation in consecutive patients referred for SNS according to antiphospholipid antibodies (aPL) status. Fifty-three Caucasian patients were enrolled from 1996 to 2001. Diagnosis of SNS was based on the presence of a widespread livedo racemosa and at least one clinical neurologic ischaemic event. The following investigations were performed: detection of antithrombin III, protein C and protein S deficiency, lupus anticoagulant, anticardiolipin and anti-beta2 glycoprotein I antibodies, biologic false-positive test for syphilis, and factor V Leiden mutation by direct genomic analysis. Fisher's test and t-test were used for statistics. Detection of aPL on multiple determinations was negative in 31 patients (group 1) and positive in 22 patients (group 2). Factor V Leiden mutation was detected in six patients (11.3%), heterozygous in all. The frequency of this mutation was statistically higher in group 1 (6/31, 19.3%) than in group 2 (0/22; P = 0.035). Within aPL-negative SNS, the comparison of patients with versus without factor V Leiden mutation showed no difference for clinical data or familial history of thrombosis. A high prevalence of heterozygous factor V mutation was found in aPL-negative patients with SNS. This finding adds further arguments to consider SNS as a heterogeneous entity.

Antiphospholipid antibodies and reproduction: the antiphospholipid antibody syndrome.

In women who have a diagnosis of APS (both clinical and laboratory criteria) the chance for successful pregnancy is reduced. In these cases, treatment appears to be a clear option, particularly in the case of prior thromboembolic events. The current preference of treatment for women with RPL and aPL antibodies is subcutaneous heparin and aspirin. This treatment should begin with a positive pregnancy test and continue postpartum. It is unclear, at this time, what treatment, if any, is required for women who do not meet all the criteria for diagnosis of APS, but who are known to have aPL antibodies. In some cases, these women were tested because of a prior false-positive test for syphilis, with subsequent identification of aPL antibodies. More recently, women undergoing IVF were tested and found to have an increased incidence of aPL antibodies. It was suggested that aPL antibodies are associated with infertility and failure to implant. However, a summary of published reports indicate that positive aPL antibodies in patients undergoing IVF do not influence ongoing pregnancy rates. This subject, however, remains an area of active investigation because aPL antibodies were shown to interact with the syncytiotrophoblast and cytotrophoblast layers and could, theoretically, after implantation.

Trends in the incidence and mortality of systemic lupus erythematosus, 1950-1992.

To describe trends in systemic lupus erythematosus (SLE) incidence and mortality over the past 4 decades. Using the Rochester Epidemiology Project resources, medical records were screened to identify all Rochester, Minnesota residents with any SLE-associated diagnoses, discoid lupus, positivity for antinuclear antibodies, and/or false-positive syphilis test results determined between January 1, 1980 and December 31, 1992. Medical records were then reviewed using a pretested data collection form in order to identify cases of SLE according to the American College of Rheumatology 1982 revised criteria for SLE. Drug-induced cases were excluded. All identified SLE patients were followed up until death, migration from the county, or October 1, 1997. These data were combined with similar data from the same community obtained between 1950 and 1979, and trends in the SLE incidence and mortality over time were calculated. Of the 430 medical records reviewed, 48 newly diagnosed cases of SLE (42 women and 6 men) were identified between 1980 and 1992. The average incidence rate (age- and sex-adjusted to the 1970 US white population) was 5.56 per 100,000 (95% confidence interval [95% CI] 3.93-7.19), compared with an incidence of 1.51 (95% CI 0.85-2.17) in the 1950-1979 cohort. The age- and sex-adjusted prevalence rate as of January 1, 1993 was approximately 1.22 per 1,000 (95% CI 0.97-1.47). Survival among SLE patients was significantly worse than in the general population (P = 0.017 compared with the 1980-1992 cohort, and P < 0.0001 compared with the 1950-1979 cohort, by log-rank test). Cox proportional hazards modeling demonstrated a statistically significant improvement in the survival rate over time (P = 0.035). Over the past 4 decades, the incidence of SLE has nearly tripled, and there has been a statistically significant improvement in survival. These findings are likely due to a combination of improved recognition of mild disease and better approaches to therapy.

False-positive tests for syphilis associated with human immunodeficiency virus and hepatitis B virus infection among intravenous drug abusers. Valencian Study Group on HIV Epidemiology.

The role of HIV, hepatitis C virus, and hepatitis B virus infections in the production of biological false-positive reactions for syphilis was evaluated in two large samples of intravenous drug abusers and homosexual men attending AIDS prevention centers in Spain. A significantly increased odds ratio (OR) for false-positive tests for syphilis [OR 2.23, 95% confidence intervals (CI) 1.76-2.83] was observed for HIV-seropositive intravenous drug abusers; biological false-positive reactions were also more frequent (OR 1.73, 95% CI 1.30-2.31) among intravenous drug abusers who were hepatitis B virus seropositive but not among those who were hepatitis C virus seropositive (OR 0.90; 95% CI 0.48-1.69). Among homosexuals, the association between HIV and biological false-positive reactions was restricted to subjects who were also intravenous drug abusers, indicating the crucial role of intravenous drug abuse. Only 20.5% of intravenous drug abusers with a previous biological false-positive reaction yielded a false-positive result in their subsequent visit.

Placental pathology in systemic lupus erythematosus and phospholipid antibody syndrome

Clinicians have long appreciated that there is increased risk of poor pregnancy outcome in women with clinical or subclinical (i.e., serological) evidence of autoimmunity. The first report of medical complications related to a circulating anticoagulant was in 195217; its presence in patients with systemic lupus erythematosus (SLE) gave rise to the term lupus anticoagulant, which is in fact a misnomer, as this phenomenon is found in patients who may not have SLE. Additionally, it is not associated with an increased predisposition to bleeding but rather a prothrombotic diathesis. Since that time, investigators have attempted to unravel the relationship between SLE, phospholipid antibodies (aPL), (which include the lupus anticoagulant, anticardiolipin antibodies [aCL], and a biologically false-positive test for syphilis [Venereal Disease Research Laboratories] and pregnancy compromise. Numerous studies show that much of the pregnancy compromise associated with SLE appears to result from disease activityZ6, 28, 72 plus or minus the presence of phospholipid antibodies., 20, 21, 39. 41, 43, 47, 49 Preterm birth is more common in lupus pregnancie~.~~ Conversely, the presence of phospholipid antibodies and antiphospholipid antibody-related pregnancy loss may also be the herald of future maternal clinical disea~e.'~, 18, 29, 3n, 5n, 51 Bagger et a1 observed while investigating the degree of association between aCL and recurrent abortion or late fetal death with other signs of autoimmune disease (particularly SLE) that aCL-positive women with recurrent abortion or late fetal death have an increased occurrence of clinical

Antiphospholipid antibodies: Basic immunology and assays

Great progress has been made within the past 10 years in characterizing, assaying,and describing mechanism(s) of action in vitro of antiphospholipid antibodies (a-PL Abs); three prominent members are reagin, anticardiolipin antibodies (a-CL Abs), and the lupus anticoagulants (LAC). The major focus of this review is on basic and current biochemical and immunologic research. First, the biochemistry, structural composition, and sources of anionic and dipolar ionic (zwitterionic) phospholipids are discussed together with several serum antibodies directed to these phospholipids. Cardiolipin, the most acidic phospholipid (net negative charge of 2 at pH 7.0) has been historically important as an antigen for testing reagin in syphilis serology, and currently is part of the antigenic composition used in the Venereal Disease Research Laboratory (VDRL) tests. In this connection, the chronic biological false-positive test for syphilis and the LAC are discussed in association with autoimmune disorders such as systemic lupus erythematosus. Second, a naturally occurring plasma anticoagulant in vitro and a critical cofactor for binding of purified autoimmune a-CL Abs to cardiolipin is considered, the β2-glycoprotein I (β2-gpl). This single-chain plasma polypeptide is highly glycosylated, has 326 amino acids, a molecular weight of 50 kD, and is characterized by repeating amino acid motifs or domains that structurally resemble multiple loops. The highly cationic C-terminal fifth domain binds to anionic phospholipids. The (β2-gpl). is a member of the short consensus repeat superfamily of proteins, and is compared with other proteins with similar domains. Third, experiments are detailed for defining LAC and distinguishing it from other a-CL Abs. Cofactors are also associated with LAC and include β2-gpl, prothrombin, protein C, protein S, tissue factor, and factor XI. Thus, LAC antibodies are heterogeneous, and no individual assay can detect all LACs. Because patients with syphilis and other infectious diseases have no cofactor associated with a-CL Abs, their plasma LACs are negative. The a-CL Abs found in infection are not associated with the clinical features of the antiphospholipid syndrome. LAC assays are important because of the pathogenetic association with clinical observations of venous and arterial thrombosis, thrombocytopenia, and recurrent fetal loss. Finally, reports leading to development of currently used direct solid-phase enzyme-linked immunosorbent assays (ELISA) for testing a-PL Abs are outlined; these developments have greatly increased understanding of the basic immunology of target antigens and their respective antibodies. Of significance, a-CL Abs cross-react with other anionic phospholipids. Additionally, the results of these assays led to the realization that high levels of circulating a-PL Abs over long periods are associated with a number of clinical problems now known collectively as the antiphospholipid syndrome.

Autoantibodies to Phospholipids and to the Coagulation Proteins in AIDS

In HIV-1 infection, an increased prevalence of anticardiolipin autoantibodies (aCL) and lupus anticoagulant (LA) has been described. In order to see if these antibodies are isolated or, like in autoimmune diseases, associated with hematological disorders and with antibodies to other phospholipids and to proteins of coagulation, we investigated 3 groups of patients: 1. 342 HIV-1 infected patients, 2. 145 control patients including 61 systemic lupus erythematosus (SLE) patients, 58 patients with a connective tissue disease, 15 patients with stroke, 11 patients with syphilis and 3. 100 blood donors. In HIV-1 infection antiprothrombin (aPrT) antibodies were present in 2% of patients, the prevalence of antiphosphatidylcholine antibodies (aPC) (50%) was almost as high as aCL (64%), and 39% had both antibodies. Absorption on liposomes of the latter revealed an heterogeneous mixture of aCL and aPC or cross-reacting antibodies. In contrast with SLE, anti-beta 2-glycoprotein I (4%), LA (1%), biological false positive test for syphilis (0.3%), thrombosis (p < 0.001) were uncommon. In HIV-1 infection, antiphospholipid antibodies do not associated with features linked to them in SLE or syphilis.

Presence of Multiple Anti-Phospholipid Antibody Specificities in a Pediatric Population

Thrombotic related events are thought to be associated with the presence of anti-phospholipid antibodies (APA). However, the association of anti-cardiolipin antibody is much weaker than the association with antibodies to other phospholipids. Much of the literature equates antiphospholipid antibodies and anticardiolipin antibodies because of the relationship of APA and false positive tests for syphilis. However, recently the presence of antibodies to naturally occurring phospholipids other than cardiolipin have been reported. In fact, some investigators report that antibodies to phosphatidylserine appear to correlate more closely to disease processes than anti-cardiolipin antibodies. We describe here the presence of non-anti-cardiolipin antiphospholipid antibodies in a pediatric population that lack anti-cardiolipin antibodies and demonstrate the association of these antibodies with thrombotic disease. Antibodies to phosphatidic acid were the most prevalent and correlated (p < .001) with thrombotic disease and idiopathic thrombocytopenia purpura. The rank order of prevalence of antibodies to phospholipids was phosphatidic acid, phosphatidylglycerol, phosphatidylinosital, phosphatidylserine, cardiolipin and phosphatidylethanolamine. Antiphospholipid antibodies of the three major sera isotypes were present in the positive sera examined. These descriptive findings suggest that the significance of APA other than anti-cardiolipin antibodies in pediatric patients should be further investigated.

Studies on cases with biological false positive tests for syphilis in human dry dock

Studies on cases with biological false positive tests for syphilis in human dry dock

Changes in clinical features of patients with systemic lupus erythematosus followed prospectively over 2 decades.

In the past decades the general concept of the disease course and the prognosis of systemic lupus erythematosus (SLE) has changed dramatically. The improvement in prognosis of our SLE patients is often said to be related to the growing awareness of the disease. This study focussed on whether or not the clinical features at the onset of the disease, and at diagnosis, and the clinical course as well as the age at the onset of the disease had changed during the past decades. No obvious differences were observed in the age at the onset of the disease or in the age at diagnosis. Of the 22 clinical signs studied, only the prevalence of Raynaud's phenomenon at the onset of the disease had increased during the past 20 years. At diagnosis, the prevalence of oral ulcers and false positive syphilis test had decreased. Only small differences in the type but not in the number of exacerbations were observed; in the past 20 years, the prevalence of renal involvement increased from 20% to 43%. However, this was not significant. Our results did not support the theory that during the past 2 decades the disease had changed in its expression, neither did we find that the disease is presently diagnosed at an earlier age, as would be expected from the increased awareness of the disease.

Significance of anti-phospholipid antibodies in patients with lupus nephritis

Anti-phospholipid antibodies (APA) as markers or mediators of thrombosis in lupus could be of pathogenetic significance in nephritis, since glomerular capillary thrombi are an indicator of subsequent renal dysfunction. Isotype specific APA antibodies were measured, using cardiolipin as the antigen, in 76 patients with lupus nephritis. Twenty-nine percent of the patients had elevated IgG APA. Overall, 43% of patients showed raised levels of at least one isotype. In general, APA had specificity for anionic phospholipids. In vitro lupus anticoagulant activity was associated with all three isotypes of APA, but only the IgM isotype correlated with the biological false positive test for syphilis. APA were not associated with thromboses or neurological involvement, and only the IgA isotype correlated with thrombocytopenia. We confirmed an association between the presence of intraglomerular thrombi and serum IgG APA. However, we found no association between APA and renal histological pattern, or long-term renal function. Our data, therefore, do not support a major pathogenetic role for APA in the nephritis of lupus in treated patients.

Cyclophosphamide Use in a Young Woman With Antiphospholipid Antibodies and Recurrent Cerebrovascular Accident

We have described a 25-year-old woman with recurrent cerebral thrombosis associated with very high levels of antibodies against phospholipids. Antinuclear antibodies and clinical features of a defined connective tissue disease were absent. Treatment with plasmapheresis, prednisone, intravenous cyclophosphamide, and warfarin was accompanied by disappearance from the serum of the lupus anticoagulant and the biologic false-positive test for syphilis; IgG anticardiolipin antibodies persisted, however, and the patient had a second cerebral thrombosis. Clinical improvement ultimately occurred after the dosage of cyclophosphamide was optimized and the level of IgG anticardiolipin antibody decreased to a level lower than any that has been previously associated with thrombotic complications.

Anticardiolipin antibodies in homosexual men: Prevalence and lack of association with human immunodeficiency virus (HIV) infection

Tests for anticardiolipin antibodies (ACL) on sera from 100 male homosexuals and 60 male heterosexuals showed that 57% of the homosexuals, in contrast to none of the heterosexuals, were ACL positive. The ACL were predominantly of the immunoglobulin G isotype and, in a high proportion of cases tested (82%), were reactive with other phospholipids, especially those with a negative charge. ACL were not related to the clinical status of the homosexuals, being evenly distributed among 40 with acquired immunodeficiency syndrome (AIDS), 20 with AIDS-related complex (ARC), 20 with asymptomatic infection with human immunodeficiency virus (HIV) and/or lymphadenopathy syndrome, and 20 who were HIV-antibody negative. Nor were they associated with thrombocytopenia, thrombosis, neurologic disease, a biological false-positive test for syphilis (BFP), or antibodies to DNA. It is concluded that factors other than infection with HIV are responsible for ACL positivity in homosexual males and that the epitopes recognized by ACL in this group are distinct from those associated with thromboembolism or the BFP reaction or cross-reactive with DNA.

Autoimmune Antibodies and Pregnancy Outcome in Women with False-Positive Syphilis Test Results: A Retrospective Controlled Investigation of Women from 5170 Deliveries

Nine pregnant women with false-positive syphilis test results, and 13 matched controls, were screened for autoimmune antibodies to ascertain whether any relationship might exist between their presence and the occurrence of obstetric problems. Investigations included assays for anti-cardiolipin antibodies (ACA), lupus anticoagulant (LAC), anti-nuclear antibodies (ANA) (including antibodies against extractable nuclear antigen), anti-smooth muscle antibodies, anti-mitochondrial antibodies, anti-DNA antibodies, IgM-RF and complement factors. We found no significant difference in the incidence of obstetric problems between the two groups. Except that significantly more women were positive for ACA in the group with false-positive syphilis tests than in the control group, there were no differences between the groups with regard to the antibodies tested for. There was only one case of SLE, a patient positive for LAC, and who had had several miscarriages and no pregnancy resulting in a live birth. Our findings suggest that it would be unwarranted to devote resources to routine screening for these antibodies in healthy women with a false-positive syphilis test result, though the presence of LAC could possibly be used as an indicator of the risk of spontaneous abortion due to SLE.

Antigens of Treponema pallidum Recognized by IgG and IgM Antibodies During Syphilis in Humans

IgG and IgM antibody specificities for antigens of Treponema pallidum Nichols strain were determined by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the western blot technique in sera from patients with untreated syphilis, normal persons, persons with biologic false-positive tests for syphilis, and sexual contacts of persons with infectious syphilis. IgG reactivities of sera from individuals with primary syphilis varied considerably but consistently exhibited strong reactivity to a 48-kilodalton band. Sera from patients with secondary and early latent syphilis uniformly demonstrated reactivity to 22 separate polypeptide antigens; decreased reactivity was seen in late latent syphilis. Normal and biologic false-positive sera showed weak IgG reactivity against none to 12 polypeptides. Sera from asymptomatic contacts of persons with infectious syphilis showed reactivity to a varying number of treponemal antigens, including some reactions not seen with normal sera. IgM reactivity was most prominent in secondary syphilis but was demonstrable at all stages of disease.

Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus.

Eight families (121 individuals) with two or more members affected with systemic lupus erythematosus (SLE) were analyzed for histocompatibility antigens (HLA-A, B, C, DR, MT, and MB) and complement antigens (C4A, C4B, and BF). These data were correlated with serological markers (antinuclear antibodies, single- and double-stranded anti-DNA, anti-SM, anti-nRNP, anti-Ro [SS-A], anti-La [SS-B], and biological false-positive tests for syphilis and clinical features. Fifteen members had SLE, and 19 had other immune diseases (subacute cutaneous lupus erythematosus, discoid lupus erythematosus, hypothyroidism, insulin-dependent diabetes mellitus, primary Sjogren's syndrome, immune thrombocytopenic purpura, rheumatoid arthritis, and multiple sclerosis). Twenty-three healthy relatives (seroreactors) had significant titers of circulating antibodies, as did 2 of 17 spouses. There was an increased frequency of null C4 alleles in those individuals with SLE (60%) and healthy relatives (50%) as compared with spouses (24%). Multivariate analysis showed a significant association between SLE and female sex (P =.006), whereas there was no significant association revealed between female sex and other immune diseases. Patients with SLE also had a higher frequency of either C4A or C4B null alleles (P = .01) than those with immune diseases. The C4A homozygous null phenotype was more common in SLE patients than in seroreactors (P = .02). There was a higher frequency of HLA-DR2 and DR3 in individuals with SLE than in those with immune disease (P = .08), seroreactors (P = .02) and normal relatives (P = .002). One totally C4-deficient patient with SLE was identified. These families demonstrate an important association between SLE and the C4 null allele and the HLA-DR2 and DR3. These risk factors, however, cannot account for the development of disease in all individuals.