Evidence Of Systemic Lupus Erythematosus Research Articles

Treatment of lupus nephritis: A meta-analysis of clinical trials

The best therapeutic choice in lupus nephritis remains shrouded in a body of controversial literature. The purpose of this review was to assess and compare by meta-analysis the efficacy of therapeutic agents used in the treatment of lupus nephritis using outcomes of end-stage renal disease (ESRD) and total mortality. An exhaustive search was performed using MEDLINE (1970 to 1995) and manual search of bibliographic notations and nonindexed sources. Twenty prospective controlled trials with treatment allocation by random assignment or consecutive enrollment were identified using diagnostic evidence of systemic lupus erythematosus based on American Rheumatism Association (ARA) criteria and clinical/biopsy evidence of lupus nephritis. One trial was excluded, resulting in 19 trials (n = 440) using treatment groups of oral prednisone alone, azathioprine with and without concomitant prednisone, oral cyclophosphamide with prednisone, azathioprine and oral cyclophosphamide with prednisone, and intravenous cyclophosphamide with prednisone. Crude risk data was pooled. An adjusted pooled risk was calculated using the random effects model of DerSimonian and Laird. Two measures of clinical effectiveness were used to compare treatments: absolute risk differences and number needed to treat. Analysis was completed between treatment groups as follows: oral prednisone compared with all immunosuppressive agents with prednisone and all treatment groups compared with one another. When compared with oral prednisone alone, immunosuppressive agents used in conjunction with oral prednisone were found to be statistically more effective for both total mortality and ESRD (absolute risk differences, 13.2% and 12.9%, respectively). When treatment groups were compared, intravenous cyclophosphamide in conjunction with oral prednisone was found to be statistically more effective than oral prednisone alone for both total mortality and ESRD (absolute risk differences, 19.9% and 16.2%, respectively). The simultaneous use of azathioprine and oral cyclophosphamide concomitant with oral prednisone was found to be 16.9% more effective than oral prednisone alone in reducing incidence of ESRD. No difference was seen in total mortality and data represented only two studies (n = 30). No immunosuppressive agent was found to be statistically more effective than another for either total mortality or ESRD. Future prospective studies are needed to control for numerous variables and renal function changes to provide more definitive answers.

The antiphospholipid/cofactor syndromes: A primary variant with antibodies to β2-glycoprotein-I but no antibodies detectable in standard antiphospholipid assays

Most systemic lupus erythematosus (SLE) patients with two or more clinical manifestations of the antiphospholipid syndrome (APS) and negative antiphospholipid antibodies (aPL) have antibodies to beta 2-glycoprotein-I (a beta 2 GP-I). Herein we describe a similar set of circumstances, but in patients without evidence of SLE. We studied 6 patients with recurrent venous and/or arterial thromboses without aPL as detected by routine assays nor clinical or serological evidence of other autoimmune disease. Immunoglobin (Ig) G and IgM antibodies to bovine and human phospholipid-free beta 2 GP-I were studied by Western blot test and by enzyme-linked immunosorbent assay (ELISA) utilizing radiated and nonirradiated plates. We also tested antibodies to cardiolipin, phosphatidylserine, and phosphatidylethanolamine by ELISA. As controls, 54 normal sera were studied. All 6 patients had recurrent arterial and/or venous thromboses. Three also had thrombocytopenia, 1 had livedo reticularis, and 2 had valvular heart disease. None of the patients had aPL, but all had serum IgG reactivity against human and bovine beta 2 GP-I (P < 0.001 versus controls for both). Titers of anti-bovine beta 2 GP-I were higher when studied in irradiated plates but were also higher than normal in nonirradiated plates (P < 0.001). These antibodies did not recognize human or bovine beta 2 GP-I bound to cardiolipin in solid phase. We confirmed by Western blot that these autoantibodies recognize human beta 2 GP-I. We found no IgM a beta 2 GP-I. We describe a primary condition akin to the antiphospholipid syndrome with negative aPL, but with serum IgG antibodies to human and bovine beta 2 GP-I. These antibodies recognize beta 2 GP-I epitopes that are not accessible when beta 2 GP-I is bound to cardiolipin.

Systemic lupus erythematosus in two adults with human immunodeficiency virus infection

T WO PATIENTS with strong clinical and serological evidence of systemic lupus erythematosus (SLE) and renal disease are presented to illustrate the difficulties of correctly diagnosing the underlying nephropathy in the presence of human immunodeficiency virus (HIV) infection. Although the first patient demonstrated typical changes consistent with SLE nephritis, the renal pathological condition in the second patient was that of collapsing glomerulosclerosis.

Neurological disorders, other than stroke, associated with antiphospholipid antibodies in childhood.

We report the results of a systematic study on the association of antiphospholipid antibodies (aPLs) with some neurological disease other than stroke in a childhood population. Patients affected by migraine, benign intracranial hypertension (BIH) or unilateral movement disorders, such as hemichorea and hemidystonia with acute-subacute onset, were screened for aPLs. None of them had clinical or serological evidence of Systemic Lupus Erythematosus (SLE) or other connective tissue disease. Moderate to high levels of anticardiolipin antibodies (aCL) and/or positive Lupus Anticoagulant (LA) were demonstrated in 6 out of 17 patients with migraine, in 3 out of 4 patients with BIH and in all of the 5 patients showing unilateral movement disorders. The association between aPLs and these neurological conditions, usually regarded as cryptogenic, may suggest a possible pathogenetic mechanism.

Myocardial Infarction as the Presenting Manifestation of Systemic Lupus Erythematosus with Antiphosphatidylserine Antibodies

The presence of antiphospholipid antibodies has been associated with thrombotic events in systemic lupus erythematosus and other diseases. Antiphosphatidylserine antibodies have been shown more recently to have clinical implications being noted in thrombocytopenia, positive VDRL test, prolonged partial thromboplastin time, and recurrent fetal loss. To report a patient with systemic lupus erythematosus who presented with a myocardial infarction resulting from a single clot in the distal left anterior descending coronary artery and to discuss the merits of evaluating such patients for the presence of antiphospholipid antibodies. Case report and review of the literature. A 55-year-old woman with no risk factors for coronary artery disease presented with a myocardial infarction. A distal left anterior descending coronary artery clot was seen on angiography. Evaluation for the presence of a hypercoagulable state revealed evidence for systemic lupus erythematosus. Although lupus anti-coagulant and anticardiolipin antibody titers were negative, antiphosphatidylserine IgA antibodies were detected. Because antiphosphatidylserine antibodies of the IgA isotype have been shown to be associated with thrombosis and other manifestations of systemic lupus erythematosus, a complete evaluation for antiphospholipid antibodies should include testing for all three isotypes.

Nephrotic syndrome related to systemic lupus erythematosus after griseofulvin therapy

We report a 16-year-old male who developed nephrotic syndrome related to membranous glomerulopathy with clinical and serological evidence of systemic lupus erythematosus after treatment with griseofulvin. To our knowledge, this is the first case of griseofulvin-exacerbated lupus in which nephrotic syndrome has been observed.

Discoid Lupus Erythematosus: Successful Treatment With Oral Methotrexate

We report an encouraging response to treatment with methotrexate in a single patient with severe discoid lupus erythematosus who did not respond to conventional therapy. <h3>Report of a Case.</h3> A 61-year-old white woman presented 7 years ago with a 39-year history of severe scarring discoid lupus erythematosus. Previous treatments included topical and intralesional steroid therapy and lowdose prednisone. Examination revealed numerous large erythematous infiltrated scaly plaques with focal areas of atrophy on the face (<b>Figure 1</b>). There was extensive scarring from previous lesions. Aside from arthralgia, there was no evidence of systemic lupus erythematosus. Initial laboratory investigations included a normal hemogram, an elevated sedimentation rate, normal renal function, negative rheumatoid factor, antinuclear antibodies, anti-DNA, and RNP and Sm antibodies. Complement studies were normal. Findings from a skin biopsy specimen were consistent with discoid lupus erythematosus. Direct immunofluorescence studies showed negative findings. Initial therapy consisted of chloroquine (250 mg, orally twice

Arthropathy in thalassaemia patients receiving deferiprone

The iron chelator deferiprone (L1) reduces tissue iron stores in iron-loaded patients. Three of sixteen patients treated with deferiprone developed joint pain and swelling without evidence of systemic lupus erythematosus (SLE). Articular cartilage, synovial hypertrophy and iron deposition, and synovial lining cell proliferation, with no inflammatory or allergic reaction, were observed on synovial exploration and biopsy. Symptoms resolved partly or completely during continued drug administration. We hypothesise that deferiprone-induced shifts of iron to synovium resulted in tissue damage, accelerated by free-radical formation during incomplete complexation of iron and this bidentate chelator. This deferiprone-associated symptom complex is not associated with drug-induced SLE, and does not progress in severity during continued therapy.

Antiphospholipid antibodies and risk of intrauterine late fetal death.

Goal of the study was to analyze the relationship between anticardiolipin antibodies, lupus anticoagulant and the risk of intrauterine late fetal death. A case-control study was conducted in a network of general and teaching hospitals in northern Italy. Cases studied were 99 women (median age 27 years), without clinical evidence of systemic lupus erythematosus or other immunological disorders who had an 'unexplained' intrauterine fetal death at or after the 20 weeks of gestation. The control subjects were 85 women (median age 28 years) who gave birth at term (> 37 weeks gestation) to healthy infants on randomly selected days at the same hospitals where cases had been identified. The presence of lupus anticoagulant was detected in four of the 99 cases (4%, 95% confidence interval 2%-15%) and none of the 85 controls. A total of 10 out of the 89 cases (11%, 95 confidence interval 6%-23%), but none of the 79 controls for whom anticardiolipin antibodies value was available had elevated anticardiolipin antibodies; this difference was statistically significant (chi 2(1) = 9.38, p < 0.01).

Cutaneous manifestations associated with antiphospholipid antibodies in patients with suspected primary antiphospholipid syndrome: a case-control study.

To study the association of a variety of dermatological manifestations related to vascular abnormalities with antiphospholipid antibodies in patients with suspected primary antiphospholipid syndrome. Case-control study. Consecutive patients referred to the coagulation and haemostasis service of a general hospital for the first determination of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) and newly diagnosed disorders (for example, thrombocytopenia, thrombotic disorders, and unexplained repeated abortions) were selected. Patients were examined by two dermatologists according to predefined criteria, and information about general characteristics and relevant dermatological and medical histories were collected using an ad hoc questionnaire. The study was limited to patients without evidence of systemic lupus erythematosus. A total of 35 patients was examined; 13 subjects were positive for lupus anticoagulant or anticardiolipin antibodies, or both (cases), and 22 were negative (controls). Moderate to severe livedo reticularis and acrocyanosis were significantly associated with antiphospholipid antibodies, with relative risks of 13.1 (95% confidence interval 1.1 to 149.0) and 8.6 (95% confidence interval 1.1 to 65.1). Capillaritis was also associated with the antibodies. Histories of Raynaud's phenomenon and superficial thrombophlebitis were more common in cases than controls. This study provides quantitative evidence of the association of antiphospholipid antibodies with several cutaneous diseases in which vascular abnormalities seem to play a major part. The study suggests that these manifestations might appear early in the development of the antiphospholipid syndrome.

Preliminary classification criteria for the antiphospholipid syndrome within systemic lupus erythematosus

Ten percent of 667 consecutive systemic lupus erythematosus (SLE) patients were considered to have definite antiphospholipid syndrome (aPLS) because they had two or more antiphospholipid (aPL)-related clinical manifestations and aPL titers more than 5 SD above the mean of normal controls. Another 14% had either one aPL-related manifestation but high titers of the antibody or two manifestations and low aPL titers (probable aPLS). One fourth of the patients had no manifestations but high titers, one manifestation and low titers, or two or more manifestations and negative aPL titers (“doubtful” aPLS); the other half were considered negative for aPLS. In patients with high-titer aPL, the number of aPL-related manifestations was influenced by disease duration and number of pregnancies, indicating potential mobility of category with time or with risk of recurrent pregnancy loss. Patients with two or more manifestations but variable aPL levels differed in immunosuppressive treatment and in the number of times they had been tested, indicating potential mobility of category with lower treatment and/or further aPL testing. Patients with definite aPLS had increased risk of cutaneous vasculitis, peripheral neuropathy, seizures, psychosis, transient ischemic attacks, and leukopenia. In 11 of 52 SLE patients with definite aPLS the initial manifestation was related to aPL, and in 16 it concurred with an unrelated one. Only two patients fulfilled criteria for aPLS before having other evidence of SLE. The authors conclude that aPLS occurring within SLE is part of the disease rather than an associated condition and propose the use of definite and probable classification categories. These criteria, with appropriate follow-up and clinical and serological exclusion clauses for potential primary conditions, could also be applied to primary aPLS.

The Lupus Anticoagulant and Dementia in Non-SLE Patients

The syndrome of circulating anticoagulants in patients without evidence of systemic lupus erythematosus (SLE) has lately become a focus of interest. The clinical features, neuroimaging findings and clinical course of 12 such patients, who presented with neurological symptoms, were analyzed. None of the patients fulfilled the American Rheumatism Association (ARA) criteria of SLE. During a follow-up period of up to 5 years, 9 patients (75%) deteriorated mentally. In 5, cerebrovascular lesions were observed clinically and/or neuroradiologically. Four patients showed slowly progressive mental decline without focal deficits on clinical examination or on CT and MR studies of the brain, except for a small cortical infarct in one case. All patients had radiological evidence of cortical atrophy. Thus, dementia may be a prominent feature among patients with the lupus anticoagulant. Possible underlying mechanisms, such as multi-infarct state, as well as an autoimmune process affecting specifically CNS structures, are discussed.

Systemic lupus erythematosus in a boy with chronic granulomatous disease: Case report and review of the literature

We describe a patient with X-linked chronic granulomatous disease (CGD) who developed systemic lupus erythematosus, which was characterized by photosensitivity, malar rash, glomerulonephritis, leukopenia, hypocomplementemia, antinuclear antibodies, and anti-double-stranded DNA antibodies, at age 3. The patient's mother is an asymptomatic carrier of CGD, and her other son (the patient's half-brother) also has CGD. Neither the mother nor the brother has clinical or serologic evidence of systemic lupus erythematosus. Previous cases of discoid lupus-like skin lesions have been reported both in carriers and in patients with CGD. Our patient represents the first reported case of an individual with convincing clinical, serologic, and pathologic evidence of systemic lupus erythematosus. The association between defective host defense mechanisms and autoimmune phenomena has been described previously in patients with Job's syndrome and in patients with B cell and T cell deficiency disorders, including the acquired immunodeficiency syndrome. The relationship between the known leukocyte defects in CGD and the pathogenesis of a lupus-like illness is unclear.

Possible Induction of Systemic Lupus Erythematosus by Valproate

Two patients developed clinical and laboratory evidence of systemic lupus erythematosus (SLE) during treatment with valproate (VPA) preparations. The first patient, a 47-year-old man, had fever, malaise, and thrombocytopenia 1 month after VPA was added to phenytoin (PHT) and primidone (PRM). He developed high titers of antinuclear antibodies (ANA) and anti-DNA antibodies, and hypocomplementemia. After discontinuation of PHT and VPA, steroid and immunoglobulin treatment was required for 4 weeks before his condition improved. The second patient, a 28-year-old woman, had been followed for idiopathic leukopenia for 3 years and had previously experienced fever and lymphadenopathy from PHT. After 4 months of divalproex therapy, she developed confusion, joint pain, and a dramatic increase in seizure frequency. She also developed high titers of ANA and anti-DNA antibodies and hypocomplementemia, along with a further decrease in white blood cell (WBC) count. These responded to steroid therapy and withdrawal of divalproex. Three months later, reintroduction of divalproex was followed by a return of ANA in low titer, which resolved after discontinuation. We believe that VPA may have caused true SLE in these patients, one of whom was probably predisposed.

Hematoxylin-Stained Bodies and Tissue LE Cells in a Skeletal Muscle Biopsy

Hematoxylin-stained bodies and tissue "LE cells" have been identified for the first time in a skeletal muscle biopsy from a 46-year-old white female with clinical and laboratory evidence of systemic lupus erythematosus. The specificity and limited usefulness of hematoxylin bodies are discussed.

The Immunohistology of IgA Nephropathy

The glomerular immunohistologic characteristics of 180 patients with IgA nephropathy (IgAN), defined by 2+ or greater (out of 0 to 4+) mesangial IgA-dominant or codominant immunostaining and no evidence for systemic lupus erythematosus, were compared with those of 84 patients with proliferative lupus glomerulonephritis and 254 patients with other forms of proliferative glomerulonephritis. The IgAN population increased in number by only 5% if the IgA immunostaining criterion was lowered to 1+, and it decreased by only 2% if IgA codominant staining was disallowed. A distinctive immunohistologic feature of IgAN in comparison with other immune complex-mediated glomerulopathies, in addition to the predominance of IgA immunostaining, was a high frequency (67%) of patients with greater lambda- than kappa-immunoglobulin light chain immunostaining. There was no correlation between the absolute or relative intensities or frequencies of IgA, IgG, or IgM immunostaining and the severity of glomerular disease; however, the presence of capillary wall immune deposits correlated with more severe disease. Terminal complement components were consistently present and were more conspicuous in more severely injured glomeruli. Immunostaining for the early classical complement activation pathway component C1q was absent or scanty in IgAN. This finding was particularly useful in the immunohistologic differentiation of IgAN from proliferative lupus glomerulonephritis, which was the form of glomerulonephritis with the greatest overlap with IgAN with respect to IgA immunostaining. When the diagnostic criteria for IgAN were 2+ or greater, dominant or codominant mesangial IgA immunostaining and less than 2+ C1q immunostaining, an immunohistologic diagnosis of IgAN was made with 98% accuracy.

Lupus anticoagulant in women with multiple spontaneous miscarriage.

A link between the presence of the lupus anticoagulant (LA) and recurrent spontaneous miscarriage exists; however, the incidence of the LA in patients with unexplained recurrent miscarriage is unknown. We have therefore investigated the incidence of the LA in women with recurrent miscarriage but without evidence of systemic lupus erythematosus or other syndromes known to predispose towards spontaneous abortion. Plasma from 29 such women was obtained and tested in the activated partial thromboplastin time (APTT), testing for correction with normal plasma if prolonged and in the dilute simplastin time test (DSTT), again mixing with normal plasma if prolonged. Using a prolongation in either/or both tests which was not corrected by mixing with normal plasma as criteria for the presence of the LA, 14 (48%) patients showed evidence for the presence of the LA. Substitution of platelet-rich plasma for phospholipid and plasma in the APTT corrected the prolonged clotting time in every patient (9/29) in which it was prolonged, further substantiating the presence of the LA. We suggest that the presence of the LA should be investigated in any patient with unexplained recurrent miscarriage.

TRIFASCICULAR BLOCK IN NEONATE OF MOTHER WITH LUPUS ERYTHEMATOSUS

Trifascicular block (TFB) is rare in newborn infants. Unlike congenital complete heart block, TFB has not been previously reported in infants of mothers with lupus erythematosus. We report a newborn male (birth weight 3.2kg) born by emergency caesarean section for fetal bradycardia. Maternal past history was unremarkable. Only during the last month of her pregnancy did she take Hydralazine 10mg QID daily for hypertension. At birth, the baby had a heart rate of 60 per minute and was given Atropine without response, but improved with Isoproterenol. With the exception of bradycardia of 68 per minute, physical findings were normal. Initial electrocardiogram disclosed trifascicular block and 2:1 second degree atrioventricular block. The next day his rhythm changed to sinus rhythm and bifascicular block which have remained throughout his life. He is now 17 months old and is completely asymptomatic. Viral cultures were negative. First antinuclear antibody titers (ANA) were positive ≥ 1:640 in both mother and baby. SSA and SSB titers were negative in both. At 6 months of age ANA titer became negative in the baby. However, a persistent maternal ANA titer of ≥ 1:640 at 16 months postpartum with mild arthralgias suggests continuing evidence of systemic lupus erythematosus.

Antinuclear antibodies during psoralens plus ultraviolet A (PUVA) therapy—are they worthwhile?

From 1979 to 1985, 497 patients with psoriasis were started on psoralens plus ultraviolet A (PUVA) therapy at Northwestern University. Two hundred sixty-nine of these received therapy for greater than 3 months and had at least two antinuclear antibody (ANA) determinations. We have found that the difference between the number of significantly positive ANAs pre-PUVA therapy (4 of 269) compared to post-PUVA therapy (16 of 269) was not statistically significant. Furthermore, of the patients who did develop a significantly positive ANA, not one was found to have any symptoms, signs, or laboratory evidence of systemic lupus erythematosus. We therefore suggest obtaining ANAs prior to initiating PUVA therapy and obtaining follow-up ANAs only if the initial ANA is significantly positive. Patients with pre-PUVA--positive ANAs can be started on PUVA therapy if there is no evidence of lupus erythematosus.

C1q nephropathy: a distinct pathologic entity usually causing nephrotic syndrome.

The presence, distribution, and intensity of glomerular C1q localization were evaluated by direct immunofluorescence microscopy in 800 renal biopsy specimens which were also studied by light and electron microscopy. Identified were 15 patients with extensive (mean: 3.6 + out of 4 +), predominantly mesangial, C1q localization along with C3 and immunoglobulins, but no evidence for systemic lupus erythematosus. Pathologically, this lesion most closely resembled lupus nephritis. Clinical and pathologic data from these 15 C1q nephropathy patients were compared to data from 30 lupus nephritis and 223 other proliferative glomerulonephritis patients, and the C1q nephropathy patients were found to be dissimilar to both groups. The 15 C1q nephropathy patients had an average age of 17.8 years, 8 males, 7 females, 9 Black, 100% had proteinuria (mean 7.5 g/d), 40% hematuria, 0% hypocomplementemia, and 0% antinuclear antibodies. By electron microscopy, 100% had mesangial dense deposits, 20% capillary wall dense deposits, and 0% endothelial tubuloreticular inclusions. Nine patients treated with steroids had no definite resolution of proteinuria. We proposed that C1q nephropathy is a distinct clinicopathologic entity, usually causing steroid-resistant nephrotic syndrome in older children and young adults.