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Azathioprine-induced aplastic anemia and fatal myelosuppression is a rare occurrence in patients with systemic lupus erythematosus (SLE). We report a case of a 53-year-old female with a normal thiopurine S-methyltransferase (TPMT) level who developed aplastic anemia within 4 weeks of azathioprine initiation, resulting in death. Physicians should be vigilant in monitoring routine blood work when administering azathioprine, a relatively common drug, in patients with SLE.

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In our earlier study, we utilized a Bayesian design to probe the association of approximately 1000 genes (approximately 10,000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

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Systemic sclerosis is a multisystem disorder of unknown etiology and involves organ systems such as the skin, peripheral vasculature, gastrointestinal tract, kidney, heart, and the lungs is observed quite frequently. In this review, we discuss the development of interstitial lung disease, one of the common pulmonary manifestations and a major cause of mortality and morbidity in this disorder. It is, however, under-recognized and diagnosed late in the course of the illness. Early use of pulmonary function tests followed by bronchoalveolar lavage in appropriate cases helps in early diagnosis. Recent studies emphasize the role of various profibrotic and inflammatory cytokines both locally in the lung and systemically in its pathogenesis. Treatment is helpful in arresting the progression if initiated early. Cyclophosphamide with or without corticosteroids given orally or as intravenous pulse may be helpful.

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Systemic lupus erythematosis (SLE) is a heterogenous disease of unknown etiology. It is not uncommon to see pleuropulmonary involvement in isolation or along with the involvement of other organ systems in SLE. Pulmonary manifestations of SLE can involve the pleura, lung parenchyma, airways, pulmonary vasculature, and the respiratory muscles. In this review we discuss two important pulmonary manifestations of SLE: acute lupus pneumonitis and diffuse interstitial lung disease. These two conditions have a major impact on the mortality and morbidity of patients with SLE and it is essential to recognize and treat them appropriately. High-resolution computed tomographic scans of the chest and pulmonary function tests help to establish a diagnosis and aid long-term follow-up of these patients. High-dose corticosteroids are the mainstay of treatment for the two conditions, although other agents such as cyclophosphamide, azathioprine, intravenous gamma globulin, and plasmapheresis have been used with varying degrees of success.

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Adult-onset Still's disease (AOSD) is a rare splenic disorder with an unknown cause. It is not uncommon for AOSD to involve other organs, such as the liver; the kidney; the bone marrow; and, less often, the lungs. In this review, we discuss the pulmonary complications of AOSD. Pulmonary involvement in AOSD usually consists of pleural effusion or transient pulmonary infiltrates, but it may become life threatening if it progresses to the adult respiratory distress syndrome. Chronic conditions, such as restrictive lung disease, have also been reported in patients with AOSD. The only treatment currently available is high-dose steroids, although other agents, such as intravenous immunoglobulin, cyclophosphamide, and azathioprine, have been tried with some success.

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We have recently reported that transforming growth factor-beta (TGF-beta) co-stimulates interleukin-2 (IL-2) activated CD8+ T cells to down-regulate antibody production. In SLE, lymphocyte production of both IL-2 and TGF-beta is decreased. Here we report that a brief treatment of PBMC from SLE patients with IL-2 and TGF-beta can result in marked inhibition of spontaneous polyclonal IgG and autoantibody production. Peripheral blood mononuclear cells (PBMC) from 12 patients with active SLE were exposed to IL-2 with or without TGF-beta for three days, washed and cultured for seven more days. The mean decrease in IgG secretion was 79%. The strongest inhibitory effect was observed in cases with the most marked B cell hyperactivity. Spontaneous production of anti-nucleoprotein (NP) antibodies was observed in four cases and cytokine treatment of PBMC decreased autoantibody production by 50-96%. IL-2 inhibited Ig production by either TGF-beta-dependent or independent mechanisms in individual patients. In a study of anti-CD2 stimulated IgG production in a patient with active SLE, we documented that IL-2 and TGF-beta reversed the enhancing effects of CD8+ T cells on IgG production and induced suppressive activity instead. These results raise the possibility that cytokine-mediated down-regulation of B cell hyperactivity in SLE may have therapeutic potential.

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Systemic lupus erythematosus (SLE) is the prototype of human autoimmune diseases. Its genetic component has been suggested by familial aggregation (lambdas = 20) and twin studies. We have screened the human genome to localize genetic intervals that may contain lupus susceptibility loci in a sample of 188 lupus patients belonging to 80 lupus families with two or more affected relatives per family using the ABI Prism linkage mapping set which includes 350 polymorphic markers with an average spacing of 12 cM. Non-parametric multipoint linkage analysis suggests evidence for predisposing loci on chromosomes 1 and 18. However, no single locus with overwhelming evidence for linkage was found, suggesting that there are no 'major' susceptibility genes segregating in families with SLE, and that the genetic etiology is more likely to result from the action of several genes of moderate effect. Furthermore, the support for a gene in the 1q44 region as well as in the 1p36 region is clearly found only in the Mexican American families with SLE but not in families of Caucasian ethnicity, suggesting that consideration of each ethnic group separately is crucial.

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OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to systemic lupus erythematosus (SLE). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American SLE cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in SLE patients compared with controls, indicating an association between these genes and SLE. No association was found between SLE and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in SLE risk, while the occurrence of these alleles together increased the odds of developing SLE by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE.

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BACKGROUND AND PURPOSE: Infection/inflammation appears to be an important predisposing risk factor for brain infarction, but little is known regarding underlying molecular mechanisms. We examined the hypothesis that patients with brain infarction preceded by infection/inflammation within 1 week could be identified by a distinctive procoagulant laboratory profile characterized by abnormalities in the protein C system and endogenous fibrinolysis. METHODS: We performed a case-control study examining the relationship between preceding systemic infectious/inflammatory syndromes and selected immunohematologic variables in 36 patients with acute brain infarction and 81 control subjects (community control subjects [n = 47] and hospitalized nonstroke neurological patient controls [n = 34]). RESULTS: The stroke group had a lower mean level of the circulating antithrombotic enzyme activated protein C (APC) (4.33 +/- 0.34% [log-transformed percentage of control value, mean +/- SD]) than community control subjects (4.51 +/- 0.27%, P < .02) or hospitalized neurological patient controls (4.57 +/- 0.31%, P < .005). The lowest circulating APC levels were found in the stroke group with antecedent infection/inflammation within 1 week preceding index brain infarction (4.23 +/- 0.4%, n = 12). Within the stroke group, circulating APC levels were inversely related to IgG isotype anticardiolipin antibody titers (r = -.55, P < .001). Only the stroke group with infection/inflammation within 1 week had elevated plasma C4b binding protein compared with control subjects (141 +/- 61% versus 112 +/- 44%, P < .05). Stroke patients with antecedent infection/inflammation had a distinctively lower ratio of active tissue plasminogen activator to plasminogen activator inhibitor (0.11 +/- 0.04, n = 9) than other stroke patients (0.19 +/- 0.06, n = 9, P < .01) and control subjects (0.22 +/- 0.16, n = 17, P < .02). CONCLUSIONS: Impairments in the protein C pathway and endogenous fibrinolysis may contribute to the increased risk for brain infarction after recent (< or = 1 week) infection/inflammation. A decrease in the circulating anticoagulant APC may be related to elevated antiphospholipid antibody titers.

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Interstitial pulmonary fibrosis and tracheobronchial sicca are the most common presentation of pulmonary involvement in primary Sjögren's syndrome. There is wide spectrum of less common manifestations, including pulmonary arterial hypertension, pseudolymphoma, pulmonary lymphoma, lymphocytic interstitial pneumonitis, amyloidosis, and pleurisy. Pulmonary function test abnormalities showing a restrictive pattern and cellular abnormalities in bronchoalveolar lavage fluid for prevalent in patients without respiratory complaints and normal chest radiographs. Long-term prospective controlled studies are needed to determine the clinical course and significance of these findings.

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OBJECTIVE: To ascertain whether there are any geographic clusters of systemic lupus erythematosus (SLE), and critically review 2 previous reports of these clusters. METHODS: A literature review of all epidemiologic surveys relevant to SLE published since 1966 was undertaken. This included a search of abstracts and reports, in addition to peer-reviewed publications. RESULTS: Two geographic clusters were identified in the literature. A report purporting that contaminated ground water in southwest Tucson, Arizona was associated with significantly increased symptoms of SLE was flawed since no patients were examined, discarded criteria were used, and incorrect definitions were employed by the nonrheumatologist authors. Another study, which identified a cluster in Nogales, Arizona, used generally valid methodology. However, the authors' conclusion that a 94/100,000 prevalence of SLE was evidence of an excessive increase in this 92% Hispanic/Native American community is not consistent with published surveys among Hispanic and Native American populations. CONCLUSION: No valid claims of SLE geographic clusters have been published.

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Human immunodeficiency virus (HIV) infection can present with musculoskeletal syndromes including systemic vasculitis. We describe vasculitis resembling polyarteritis nodosa (PAN) in 2 HIV-infected individuals and review reported cases to emphasize clinical features. Our patients presented with digital gangrene and had vasculitis confirmed by angiography. In reports in the literature, patients have presented with digital ischemia and gangrene, peripheral neuropathy and constitutional symptoms. The diagnosis has been confirmed by angiography and by nerve and muscle biopsy. Treatment with systemic corticosteroids has afforded short term benefits to patients; however the effectiveness of alternative therapy and longterm prognosis remain unclear.

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A patient with hyperglobulinemic purpura of Waldenstrom and systemic lupus erythematosus is reported. The coexistence of these two conditions which share a number of common clinical and laboratory features is rare. Treatment of the patient with prednisone, colchicine and hydroxychloroquine led to the improvement of the cutaneous vasculitis and a drop in ESR, serum gamma globulins and IgM and IgG rheumatoid factors. The features of nine other cases and the immunopathogenesis of the disease are reviewed.

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Budd-Chiari syndrome, hypertension, and thrombocytopenia developed in a 6-year-old girl as manifestations of primary antiphospholipid antibody syndrome (APS). She improved with systemic corticosteroid and anticoagulation therapy. Anticardiolipin antibodies were found in the patient, her mother and 3 siblings, suggesting the importance of genetic factors. The clinical features of an APS in children is reviewed.

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Lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine were studied in 18 female patients with systemic lupus erythematosus (SLE) with mild or inactive disease. Patients were case matched (200-400 mg hydroxychloroquine daily vs no hydroxychloroquine) on several factors including daily corticosteroid dose in this cross sectional study. All had normal menstrual cycles; none smoked, used alcohol, were taking lipid altering medications or had other concurrent diseases. Patients taking hydroxychloroquine had 35-54% lower total triglyceride, VLDL-triglyceride, LDL-triglyceride, HDL-triglyceride, VLDL-cholesterol, and apolipoprotein CIII levels (p < 0.03). These results are encouraging in that hydroxychloroquine, in addition to being useful for alleviating the primary symptoms of SLE, may also be useful for ameliorating the adverse effects of corticosteroid therapy on triglyceride-rich lipoprotein metabolism.

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To determine the utility of magnetic resonance imaging (MRI) of the brain in diagnosing active neuropsychiatric disease in systemic lupus erythematosus (NP-SLE), a prospective study of 51 hospitalized systemic lupus erythematosus (SLE) patients during 64 separate episodes of suspected NP-SLE was initiated. In addition to standard hematology, chemistry, and serological tests, the workup included MRI in all patients. A computed tomographic scan of the brain was obtained in patients enrolled in the first year of the study. Of the 64 neuropsychiatric episodes, 42 were attributable to NP-SLE and 22 were attributed to causes other than SLE. Neuropsychiatric complaints unrelated to lupus included depression (n = 6), seizures (n = 5), headache (n = 3), altered mental status (n = 2), aseptic meningitis (n = 2), cardiovascular accident (n = 2), transient ischemic attack (n = 1), and vertigo (n = 1). The MRI was abnormal in 34 of 64 (53%) episodes. MRI abnormalities were more common in patients with focal neurological deficits (19/26) than in those without focal findings (15/38; P = .008) and in patients with nephritis (19/24) than in those without renal disease (15/40; P = .002). MRI abnormalities were as frequent in NP-SLE (25/42) as in cases with non-NP-SLE-related causes (9/22). Periventricular increased signal (PIS) was a frequent MRI finding (10/64). Enlargement of the prepontine cistern, an MRI finding not previously described in NP-SLE, was seen (14/64). Both findings were associated with the presence of hypertension and lupus nephritis. PIS similar to that seen in our patients has been described in otherwise healthy elderly individuals with risk factors for stroke, suggesting that vascular abnormalities may be important in the etiology of these lesions. In conclusion, abnormalities in brain MRI occur frequently in NP-SLE, especially in patients with focal neurological deficits. However, the presence of similar MRI abnormalities in SLE patients with neuropsychiatric symptoms and findings with non-SLE-related causes limits the specificity of the MRI for diagnosing NP-SLE.

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BACKGROUND AND PURPOSE: Delayed ischemic deficits contribute to the high morbidity and mortality rates associated with subarachnoid hemorrhage. We evaluated the potential usefulness of measuring coagulation and hemorheological variables and cardiolipin antibodies for prediction of delayed ischemic deficit after subarachnoid hemorrhage. METHODS: Consecutive patients with subarachnoid hemorrhage were studied. Coagulation and hemorheological variables and cardiolipin antibodies were measured on admission, within 7 days of subarachnoid hemorrhage. A subset of patients was studied on admission and at two subsequent occasions. RESULTS: Sixty-nine patients were studied. Sixty-one of these were without clinical manifestations of vasospasm at admission, and 16 developed delayed ischemic deficit during their hospitalization. None of the laboratory variables measured were significantly different between patients with or without later development of delayed ischemic deficit. Elevation of the fibrin fragment D-dimer was found in the group of eight patients admitted with ischemic symptoms and in 49% (34 of 69) of all patients, but this was not associated with delayed ischemic deficit. Sixteen patients were studied on three occasions; this group showed a significant decrease in hematocrit, an increased white blood cell count, and no change in fibrinogen concentration. Fibrin D-dimer levels rose significantly after surgery (from 5.01 +/- 0.69 to 5.53 +/- 0.58 ln-ng/ml, p less than 0.025) and after onset of delayed ischemic deficit (from 4.71 +/- 0.64 to 5.84 +/- 0.34 ln-ng/ml, p less than 0.01). CONCLUSIONS: Hemostatic measurements, hemorheological variables, and cardiolipin immunoreactivity did not predict delayed ischemic deficit in this population.

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We evaluated 50 consecutive patients with acute ischemic stroke to assess the prevalence of systemic infection preceding the neurological event. We analyzed the immunohematologic characteristics of patients with and without signs and/or symptoms of a preceding infectious process. Patients were examined less than or equal to 7 days after cerebral infarction and evaluated for fibrinogen, anticardiolipin antibodies, fibrin D-dimer (a fragment of cross-linked fibrin), plasminogen activator inhibitor-1, and protein S. Of the 50 patients, 17 had symptoms of infection beginning less than or equal to 1 month before the stroke (11 had upper respiratory tract infections, three urinary tract infections, two subacute bacterial endocarditis, and one pneumonia). Compared with patients without infection, patients with infection had significant increases in fibrin D-dimer concentration (5.3 +/- 1.1 versus 4.7 +/- 0.9 log-transformed ng/ml, p less than 0.05) and cardiolipin immunoreactivity, IgG isotype (1.8 +/- 1.3 versus 1.1 +/- 0.9 log-transformed phospholipid units, p less than 0.04), and, when studied less than or equal to 2 days after the stroke, increased fibrinogen levels (459 +/- 126 versus 360 +/- 94 mg/dl, p less than 0.05). In conclusion, infection-associated cerebral infarction is common and is associated with substantial immunohematologic abnormalities.

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We describe a patient in whom nephrotic syndrome due to renal amyloidosis occurred 4 years into the course of severe ankylosing spondylitis with peripheral joint and extraarticular involvement. Treatment with colchicine was accompanied by reversal of proteinuria, and histologic regression of amyloid deposits was documented from bone marrow obtained from the femoral heads during total hip arthroplasties staged 1 year apart.

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