Childhood agricultural and adult occupational exposures to organic dusts in a population-based case-control study of systemic lupus erythematosus.

Organic dust exposure can influence the development and symptoms of immune-related diseases such as atopy and asthma, but has rarely been examined in relation to systemic autoimmunity. The present analyses explore the association of lifetime farm and occupational organic dust exposures with systemic lupus erythematosus (SLE) in recently diagnosed patients (n = 265) compared with controls (n = 355) frequency matched by age, sex and state. Questionnaire data included childhood farm residence, childhood and adult experience with specific crops, and adult work in textiles, hog or poultry processing and paper or furniture manufacture. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression models including age, sex, state, race, education and silica exposure. Overall childhood or adult farm contact and childhood farm residence were not associated with SLE. Farm contact with livestock was inversely associated with SLE (OR = 0.55, 95% CI 0.35, 0.88). This effect was most pronounced among those with childhood farm residence and both childhood and adult livestock exposure (OR = 0.19; 95% CI 0.06, 0.63), but was difficult to separate from adult exposure to grains or corn. Other adult occupational exposures were not associated with SLE risk overall, regardless of childhood farm residence or livestock exposure, although an inverse association was seen among non-smokers (OR = 0.59; 95% CI 0.33, 1.1), particularly for textile work (OR = 0.34; 95% CI 0.19, 0.64). These exploratory findings support the development of studies to specifically investigate the effects of organic dust exposure on SLE risk, with particular attention to exposure assessment and characterization of demographics, smoking and other occupational exposures.

CTLA-4 gene polymorphisms and systemic lupus erythematosus in a population-based study of whites and African-Americans in the southeastern United States.

Cytotoxic lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activation, and may help to limit T cell response under conditions of inflammation. Genetic variability in CTLA-4 has been implicated in the development of several autoimmune diseases. Some studies have described associations between CTLA-4 polymorphisms and systemic lupus erythematosus (SLE), but findings have been inconsistent. We examined polymorphisms in the CTLA-4 gene promoter region (-1722T/C, -1661 A/G, -318C/T) and exon I (+49G/A) with respect to SLE in a population-based case-control study in the southeastern US. Genotypes from 230 recently diagnosed cases and 276 controls were examined separately for African-Americans and whites. We observed no overall associations between SLE and the four CTLA-4 polymorphisms examined. Subgroup analyses revealed effect modification by age for the presence of the -1661G allele, yielding a significant positive association with SLE in younger (<35 years) African-Americans (OR = 3.3). CTLA-4 genotypes also interacted with HLA-DR2 and GM allotype to contribute to risk of SLE. These findings suggest allelic variation in this region of CTLA4 is not a major independent risk factor for SLE, but may contribute to risk of disease in younger African-Americans or in the presence of certain immunogenetic markers.

Systemic lupus erythematosus and genetic variation in the interleukin 1 gene cluster: a population based study in the southeastern United States.

BACKGROUND: Interleukin (IL)1alpha and IL1beta, and their endogenous receptor antagonist (IL1Ra), have been related to the pathology of systemic lupus erythematosus (SLE), but the role of IL1 polymorphisms in the aetiology of SLE is unknown. OBJECTIVE: To examine polymorphisms at IL1alpha -889(C-->T), IL1alpha +4845(C-->T), IL1beta -511(C-->T), IL1beta +3953(G-->T), and IL1Ra (86 bp VNTR) in a population based study of SLE in North Carolina and South Carolina. METHODS: Genotypes from 230 cases who met ACR classification criteria, and from 275 controls matched for age, sex, and state, were analysed separately for African Americans and whites. Odds ratios (ORs) were estimated by logistic regression models for each locus alone and also after adjusting for polymorphisms at adjacent loci. RESULTS: An increased risk of SLE for the IL1alpha -889C/C genotype compared with carriage of the -889T allele was found in both African Americans (OR = 3.1, p = 0.001) and whites (OR = 2.9, p = 0.005). In African Americans, carriage of the IL1beta -511T allele was associated with a higher risk of SLE than carriage of the -511C/C genotype (OR = 2.4, p = 0.017), independent of variation at IL1alpha -889. CONCLUSIONS: The observed associations support the hypothesis that genetic variation in IL1 is involved in the aetiology of SLE and merit further investigation.

Differences by race, sex and age in the clinical and immunologic features of recently diagnosed systemic lupus erythematosus patients in the southeastern United States.

We examined the prevalence of clinical and immunologic features of systemic lupus erythematosus (SLE) by race, sex and age in a population-based study of 265 SLE patients. Patients fulfilled the American College of Rheumatology classification criteria. The median time between diagnosis and study enrollment was 13 months. The clinical and hematologic data were limited to occurrences up to 6 months after the diagnosis date, as documented in medical records. We used sera collected at study enrollment from 244 (92%) patients for serologic testing of autoantibodies. The associations between clinical and immunological features of SLE and age, sex and race were examined using logistic regression. The effect of each of these variables was examined adjusting for the other two demographic factors. Mean age at diagnosis was 6 years younger among African-Americans and other minorities compared with white patients (P < 0.01). Discoid lupus, proteinuria, anti-Sm and anti-RNP autoantibodies were more commonly seen in African-American patients, with odds ratios higher than 3.0. Photosensitivity and mucosal ulcers were noted less often in African-American patients. Proteinuria, leukopenia, lymphopenia and thrombocytopenia were approximately three times more common in men compared with women. The prevalence of oral or nasal ulcers and anti-DNA autoantibodies declined with age. The extent to which the differences we observed reflect genetic or environmental influences on the disease process should be investigated.

Immunoglobulin GM and KM allotypes in systemic lupus erythematosus.

Genetic variation in immunoglobulin gamma (GM) and kappa (KM) chains was associated with systemic lupus erythematosus (SLE) in some studies. However, the data are conflicting, and only one study examined associations in African-Americans. We examined GM and KM allotypes, by race, in a population-based case-control study of SLE. Sera from patients (n = 222) and controls (n = 273) were typed for GM and KM allotypes by a hemagglutination inhibition method. GM phenotypes were not significantly associated with SLE in African-Americans or Caucasians. However, the frequency of KM phenotypes in Caucasian patients was significantly different from that in controls (p = 0.032). KM3,3 was associated with an increased risk, whereas KM1,3 was associated with a lower relative risk of SLE. In African-Americans, however, the pattern of associations with KM phenotypes differed from that in Caucasians, and the overall difference between patients and controls was not statistically significant.

Smoking and use of hair treatments in relation to risk of developing systemic lupus erythematosus.

OBJECTIVE: To examine the association between smoking and hair treatments (dyes, permanents) and risk of developing systemic lupus erythematosus (SLE). METHODS: Patients (n = 265) diagnosed between January 1, 1995, and July 31, 1999, were recruited through 4 university based and 30 community based rheumatology practices in eastern North Carolina and South Carolina. Controls (n = 355) were identified through driver's license records and were frequency matched to patients by age, sex, and state. Data collection included a 60 min in-person interview. Analyses were limited to experiences that occurred before age at diagnosis (patients) or reference age (controls). Because the prevalence of use of hair treatments among men was very low, the analyses of those exposures were limited to women. RESULTS: There was no association with smoking history and risk of developing SLE when analyzed as status (current, former, or never-smoker) or measures of dose (duration or pack-years). Use of permanent hair dyes in women was associated with a small increased risk of developing SLE (OR 1.5, 95% CI 1.0, 2.2). This association increased with longer duration of use (compared with nonusers, OR 1.7, 95% CI 1.0, 2.7 for 6 or more years). There was little evidence of an association between SLE and use of temporary dyes or of permanents and straighteners. CONCLUSION: These results suggest at most a weak association between SLE risk and permanent hair dyes or smoking. Genetic variability in the metabolism of these products may be important to assess in future studies.

Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.

Salicortin: a repeat-attack new-mechanism-based Agrobacterium faecalis beta-glucosidase inhibitor.

Salicortin, a natural product abundant in most members of the Salicaceae family, is a mechanism-based inactivator of Agrobacterium faecalis beta-glucosidase. Inactivation is delayed in the presence of competitive inhibitors, thereby demonstrating the requirement for an enzyme-bound salicortin before inactivation. Product studies suggest that inactivation proceeds via a quinone methide intermediate formed by the fragmentation of the aglycone of salicortin while it is bound to the enzyme. Tryptic digest and HPLC/MS studies confirm the role of quinone methide attack and also show that the enzyme undergoes multiple modifications. In addition, when the inactivation was run in the presence of a mutant inactive form of the enzyme, HPLC/MS analyses clearly showed no modification of the mutant enzyme, demonstrating that the quinone methide does not exist in free solution and suggesting that inactivation is active-site directed.

Pristane induces high titers of anti-Su and anti-nRNP/Sm autoantibodies in BALB/c mice. Quantitation by antigen capture ELISAs based on monospecific human autoimmune sera.

Autoantibodies to Su and anti-nRNP/Sm are common in human and murine systemic lupus erythematosus (SLE), and are also produced by BALB/c mice with SLE-like autoimmunity induced by pristane. Antigen capture ELISAs employing monospecific human autoimmune IgG were developed to quantitate the production of anti-Su and anti-nRNP/Sm autoantibodies in 77 sera from BALB/c mice with pristane-induced autoimmunity. The sensitivity and specificity of the anti-Su antigen capture ELISA were 100% compared with immunoprecipitation of 35S-labeled cellular proteins. All 16 immunoprecipitation positive sera were positive in the anti-nRNP/Sm antigen capture ELISA (100% sensitivity), whereas 55/61 immunoprecipitation negative sera were negative by ELISA (90% specificity). The 6/61 immunoprecipitation negative sera that were ELISA positive were probably true positives because subsequent sera obtained from the same mice were positive by both techniques. Thus, the antigen capture ELISA may be somewhat more sensitive than immunoprecipitation. The titers of anti-Su and anti-nRNP/Sm positive antibodies in the sera were as high as 1:25,000-1:250,000 by ELISA, suggesting that autoantibodies may be produced in pristane-primed BALB/c mice at levels comparable to those seen in spontaneous autoimmune disease. We conclude that antigen capture ELISAs based on human autoimmune sera were highly sensitive and specific for detecting murine anti-Su and anti-nRNP/Sm antibodies. This technique will be useful for quantitating antibodies in murine autoimmune disease models, since antigen capture ELISA avoids the use of denatured or recombinant antigens, permitting antibodies recognizing tertiary and quaternary structures to be detected.

Characterization of the Su antigen, a macromolecular complex of 100/102 and 200-kDa proteins recognized by autoantibodies in systemic rheumatic diseases.

The Su autoantigen was characterized biochemically using human and murine autoimmune sera and the clinical significance of anti-Su antibodies was studied in 236 Japanese and 160 American patients with systemic rheumatic diseases. Anti-Su in immunodiffusion (ID) was strongly associated with immunoprecipitation of one or more 100- to 102-kDa proteins by MRL/lpr mouse sera (27/32 of ID positive vs 4/20 of ID negative, P = 0.000016), and all four human anti-Su reference sera immunoprecipitated the 100/102-kDa protein(s). In addition, all sera immunoprecipitated a less efficiently labeled approximately 200-kDa protein that comigrated on sucrose density gradients with the 100/102-kDa proteins. Based on these data, a complex of the 100/102-kDa and 200-kDa proteins is likely to be the main target of anti-Su antibodies. Three of four anti-Su monospecific sera were negative for immunofluorescent antinuclear antibodies (ANA), suggesting anti-Su antibodies may be associated with a negative ANA in some cases. Autoantibodies to Su were detected frequently by immunoprecipitation in systemic lupus erythematosus (17-21%), scleroderma (13-20%), and overlap syndrome (22-40%) and were associated with autoantibodies to Ku.

Synovial cysts and ganglia: the value of magnetic resonance imaging.

Synovial and ganglion cysts commonly present in close proximity to joints and skeletal structures in rheumatic disorders. Familiarity with the presentation of these soft tissue masses can facilitate timely diagnosis and effective management, thus avoiding costly and potentially high-risk procedures to patients. Management usually consists of local, nonsurgical approaches. A patient with chronic joint deformities and clinical features primarily consistent with mixed connective tissue disease is described. Multiple localized masses developed at her right elbow and were identified on T2-weighted magnetic resonance imaging as multiloculated cysts that dissected from the elbow joint. The cysts were treated successfully by needle aspiration and intraarticular corticosteroid injection. The clinical associations, diagnosis, treatment, and management of synovial cysts and ganglions are reviewed.

Diagnosis of inflammatory myopathy by percutaneous needle biopsy with demonstration of the focal nature of myositis.

Inflammatory myopathies are a group of acquired disorders with histologic features of inflammation and nonspecific myopathic changes in the muscle fibers. Up to 25% of patients with clinical features of polymyositis reportedly have no inflammatory changes in their muscle biopsy specimens, but the absence of inflammatory infiltrates does not exclude an inflammatory myopathy. However, whether the lack of inflammation is caused by sampling variation or by a total lack of demonstrable inflammation in a particular patient has been unclear in the literature. The authors diagnosed polymyositis in six patients who underwent percutaneous muscle biopsy using a Bergstrom needle. Through one skin incision, the needle was inserted into different areas within the muscle compartment, obtaining three or four concurrent specimens from each patient. In all cases of needle biopsy, adequate tissue was obtained for histochemical and electron microscopic examination. All patients tolerated the procedure well and resumed normal daily activities the morning after biopsy. Although we saw inflammatory changes in at least one biopsy specimen from each patient, one or more of the remaining specimens contained no evidence of inflammation. This illustrates that inflammatory infiltrates can be focal in polymyositis. Because a specific diagnosis of inflammatory myopathy cannot be made in the absence of demonstrable inflammation, the diagnostic yield of multiple percutaneous needle biopsy specimen is potentially higher than that of the traditional single biopsy specimen obtained with the open surgical method.

Cardiac tamponade and pericardial disorders in connective tissue diseases: case report and literature review.

Pericardial disorders occurring in connective tissue diseases are not uncommon and may present as acute or chronic pericarditis with or without an effusion. In many instances, a diagnosis of pericardial involvement is not found until autopsy. Echocardiography and other currently employed radiographic techniques have enhanced the ability to make a diagnosis. Approximate frequencies of common connective tissue disorders with pericardial involvement include scleroderma (59%), systemic lupus erythematosus (44%), mixed connective tissue disease (30%), rheumatoid arthritis (24%), and polymyositis/dermatomyositis (11%). Cardiac tamponade or constriction is rare. This article describes a patient with clinical features consistent with mixed connective tissue disease that presented with a pericardial effusion and cardiac tamponade. In addition, a review of pericardial involvement in connective tissue diseases and the occurrence of cardiac tamponade or constriction is included.

MRL mice produce anti-Su autoantibody, a specificity associated with systemic lupus erythematosus.

Certain autoimmune mouse strains exhibit features similar to human SLE. To discover genetic and immunologic events governing expression of a new SLE-associated antibody, the presence of anti-Su and its relationship to other SLE-related antibodies (anti-Sm, -ribonucleoprotein, -Ro (SS-A), -La (SS-B)) were determined in MRL and other autoimmune and nonautoimmune mice. By double immunodiffusion, sera from 34/183 (19%) 4- to 10-mo-old MRL/Mp-lpr/lpr (MRL/lpr) and 28/108 (26%) 8- to 20-mo-old MRL/Mp(-)+/+ (MRL/+) mice were positive for anti-Su antibodies. Anti-Sm antibodies were found in 60/183 (33%) and 39/108 (36%) of these animals, respectively. The two specificities were found together in individual mice more frequently than would be predicted by chance. In contrast, C57BL/6-lpr/lpr (B6/lpr) mice rarely showed either specificity. Analysis of F1 hybrids between B6/lpr and MRL/lpr and of F1 x MRL/lpr backcross mice suggested that a small number of autosomal recessive genes controlled the anti-Su and anti-Sm responses. With the exception of a single NZB serum sample, NZB, BXSB, and nonautoimmune mice were negative for all antibodies tested, and no mice were positive for anti-RNP, anti-Ro, or anti-La. MRL/lpr and MRL/+ autoimmune mice thus provide unique models for human SLE, because they express several of the SLE-specific marker autoantibodies. These models should be useful in disclosing molecular and immunologic events governing autoantibody expression in this condition.

Extraction and differentiation of the Su autoantigen from calf thymus nuclei.

Antibodies to Su antigen have been reported previously as a distinct antigen-antibody system associated with connective tissue diseases; most specifically systemic lupus erythematosus and undifferentiated connective tissue disease. The Su antigen was first identified by double immunodiffusion using calf thymus nuclear extract (CTNE) as a source for Su antigen. In this report, enhanced extraction of Su antigen was achieved using deoxyribonuclease I (DNase) for preparation of CTNE. Only the Sm antigen was found in comparable quantities in the DNase CTNE. Western immunoblotting and immunoprecipitation employing DNase CTNE and extracts of [35S]methionine-labeled HeLa cells respectively were used for further characterization and differentiation of the Su antigen. Sera from patients positive for Su antibodies by double immunodiffusion were found to react most specifically with antigen components in a molecular weight range of approximately 50-55 kDa. These methods should assist in further understanding the biochemical properties of the Su antigen.

Thoracolumbar compression fractures presenting with an acute ileus.

Corticosteroids are commonly used in the treatment of connective tissue diseases such as systemic lupus erythematosus. Although they are usually efficacious, osteoporosis leading to spine compression fractures is not uncommon. In this case report, we describe an elderly patient with systemic lupus erythematosus on long-term corticosteroid therapy who presented with symptoms of acute abdomen with minimal low back symptoms. No intraabdominal process was found by abdominal studies and exploratory laparotomy. Increased lower back symptoms led to further skeletal spine studies, which initially demonstrated a compression fracture at the twelfth thoracic (T12) vertebra. Later, a T8 and a fourth lumbar (L4) compression fracture were also found. Her abdominal and lower back symptoms resolved on conservative therapy. Although the rate of these occurrences are unknown, compression spine fractures should be considered in elderly patients presenting with acute abdomen after being on long-term corticosteroid therapy.