High Titers Of Antinuclear Antibodies Research Articles

Clinical and Prognostic Significance of Parotid Scintigraphy in 405 Patients with Primary Sjögren’s Syndrome

To evaluate the association between the degree of involvement shown by parotid scintigraphy at diagnosis and the disease expression, outcomes, and prognosis of primary Sjögren's syndrome (SS). All patients consecutively diagnosed with primary SS in our department between 1984 and 2008 were evaluated. The scintigraphic stages were classified into class 4 (severe involvement), class 2-3 (mild to moderate involvement), and class 1 (normal results). A total of 405 patients with primary SS underwent parotid scintigraphy at diagnosis (47 had class 1 involvement, 314 had class 2-3, and 44 had class 4). Patients with class 4 had a higher frequency of parotid enlargement (p < 0.001), systemic involvement (p = 0.007), high titers of antinuclear antibody (p = 0.016), positive rheumatoid factor (p = 0.002), anti-Ro/SSA (p = 0.001), anti-La/SSB (p = 0.001), low C4 levels (p = 0.001), and low CH50 (p = 0.001) in comparison with the other 2 groups. A higher rate of lymphoma development was observed in patients with class 4 involvement. Adjusted multivariate Cox regression analysis showed a hazard ratio (HR) of 10.51 (p = 0.002) and Kaplan-Meier analysis a log-rank of 0.0005. Mortality was 5-fold higher in patients with class 4 involvement. Adjusted multivariate Cox regression analysis showed an HR of 5.33 (p = 0.001) and Kaplan-Meier analysis a log-rank of 0.033. Patients with SS presenting with severe scintigraphic involvement at diagnosis had a more pronounced autoimmune expression, a higher risk of developing systemic features and lymphoma, and a lower survival rate. Study of the degree of salivary gland dysfunction at diagnosis by parotid scintigraphy offers valuable clinical information on the prognosis and outcome of primary SS.

Systemic lupus erythematosus after thymectomy for myasthenia gravis: a case report and review of the literature

Here, we report a case of systemic lupus erythematosus in a 13-year-old girl who developed the disease 3 years after thymectomy performed for the treatment of myasthenia gravis. The presenting symptoms were fever, generalized fatigability, bilateral loin pain, weight loss, arthralgia, hair loss, and recurrent painless mouth ulcers. Laboratory findings revealed proteinuria, hematuria, anemia, leucopenia, a high titer of antinuclear antibodies (ANA), anti-dsDNA, and decreased complement (C3 and C4) levels. There was minimal ascitis and pericardial effusion. Renal biopsy showed lupus nephritis class IV. The diagnosis of systemic lupus erythematosus was established based on the clinical and laboratory findings. The activity of systemic lupus erythematosus was controlled by pulsed treatment with methyl prednisolone followed by long-term oral glucocorticoid and immunosuppressive therapy. This study highlights the immune system derangement following thymectomy. It also examines the relevant literature.

An unusual case of undifferentiated connective tissue disease presenting as cardiac tamponade

Cardiac tamponade as an initial manifestation of undifferentiated connective tissue diseases (UCTD) is extremely rare, with only one case reported in literature thus far. We describe here, a case of a middle-aged man who presented with symptoms of fatigue, exertional dyspnea and orthopnea. His physical exam was significant for anasarca, elevated JVP and pulsus paradoxus. Chest X-ray showed pleural effusions and cardiomegaly, electrocardiogram revealed electrical alternans and a transthoracic echocardiogram demonstrated massive pericardial effusion with hemodynamic compromise. There was clear evidence of tamponade on right heart catheterization. All common causes of pericardial effusion were assiduously excluded before working up the patient for connective tissue disorders, which revealed a high antinuclear antibody titer (1:160), grossly elevated SSA, SSB antibodies and increased C-reactive protein levels (13.04 mg/dl). Patient had no signs or symptoms suggestive of systemic sclerosis (xerophthalmia or xerostomia) and did not meet criteria for any other known connective tissue diseases. He was therefore diagnosed with UCTD, and successfully treated with colchicine after emergency pericardiocentesis. This case presents UCTD as a rare cause of cardiac tamponade and large pericardial effusions and suggests that colchicine can be used to treat UCTD-associated effusions. These patients once diagnosed, are at risk of developing known connective tissue diseases within 5 years of disease onset and should be followed up in clinic periodically.

Discoid lupus erythematosus in a patient with scleroderma and hepatitis C virus infection

A 49-year-old Japanese woman presented with discoid lupus erythematosus (DLE) on the face. The presence of Raynaud's phenomenon, swollen fingers, a high anti-nuclear antibody titer, and the results of a biopsy revealed limited-type systemic sclerosis (lSSc). The association of SSc with DLE is rare, although some single case reports have been published in Japan. Our patient was positive for hepatitis C virus infection. Racial predisposition and immune imbalance are proposed to have played a role in the development of these lesions in our case.

Heterogeneous Nuclear Ribonucleoprotein H1, a Novel Nuclear Autoantigen

Serum samples from patients with autoimmune connective tissue diseases that show a finely speckled antinuclear antibody (ANA) on indirect immune-fluorescence often have antibodies against unknown nuclear target antigens. To search for such autoantigens we applied a proteomic approach using sera from patients with a high ANA titer (>or=640) and finely speckled fluorescence but in whom no antibodies to extractable nuclear antigens (ENA) could be identified. Using an immunoproteomics approach we identified heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) as a novel nuclear target of autoantibody response. Recombinant rat hnRNP H1 reacted in Western blot analyses with 48% of 93 sera from patients with primary Sjögren syndrome and with 5.2% of 153 sera from patients with other connective tissue diseases (diseased controls). For comparison, the diagnostic sensitivity and specificity of anti-Sjögren syndrome A (SSA) antibodies for primary Sjögren syndrome in the same patient cohort were 88.2% and 76.3%, respectively. Interestingly, 5 of 11 primary Sjögren syndrome patients with no anti-SSA or anti-SSB antibodies had anti-hnRNP H1 antibodies. Anti-hnRNP H1 antibodies were preabsorbed by hnRNP H1, as demonstrated by indirect immunofluorescence. In an evaluation of the presence of anti-hnRNP H1 antibodies in 188 consecutive samples submitted to the clinical laboratory with positive ANA (titer >or=160), anti-hnRNP H1 antibodies were found in 3 of 7 (2 primary and 5 secondary) Sjögren syndrome patients and in 8.3% of the diseased controls. HnRNP H1 is a newly discovered autoantigen that could become an additional diagnostic marker.

High frequency of Smith autoantibodies in Omani patients with systemic lupus erythematosus

This study was conducted to investigate the frequency and significance of some antinuclear autoantibodies in Omani patients with systemic lupus erythematosus (SLE). Anti-nuclear antibodies (ANA), anti-double stranded-DNA (anti-dsDNA), and anti-Smith (anti-Sm) autoantibodies were investigated in 60 Omani patients clinically diagnosed with SLE according to the American College of Rheumatology Criteria. The SLE group included 57 females and 3 males with an average age of 26 years. In addition, a group of 60 healthy Omanis (26 females and 34 males; average age 25 years) was used as a control. ANA patterns and autoantibody profile were assayed by indirect immunofluorescence assay using Hep-2 cells and liver/kidney/stomach tissue, respectively. Anti-dsDNA were examined by enzyme-linked immunosorbent assays; anti-Sm antibodies were measured by immunoblotting technique. Out of the 60 SLE patients, 59/60 (98.3%) were seropositive for ANA. Anti-dsDNA and anti-Sm each was detected in 50/60 (83.3%) of the Omani patients. The homogenous pattern of ANA was detected in 30/60 (50%) of patients, whereas the frequency of fine-speckled and coarse-speckled was 16/60 (26.7%) and 6/60 (10%), respectively. High titers (≥ 1:320) of ANA was detected in 56/60 (93.3%) of SLE patients. High titers of anti-Sm were detected in 22/60 (33.3%) of patients. High titers (>100 IU/ml) of anti-dsDNA were detected in 40/60 (66.7%) of patients. In the control group, ANA were detected in 8/60 (13.3%) but at low titers, whereas anti-dsDNA and anti-Sm were not detected in the healthy control group. This study shows that anti-Sm is as important as the anti-dsDNA for confirming the diagnosis of SLE and that anti-Sm occurs at a much higher frequency (83.3%) than that reported in other populations indicating the importance of this specific autoantibody for the diagnosis and possibly prognosis of Omani SLE patients.

Surgical result of critical limb ischemia due to tibial arterial occlusion in patients with systemic scleroderma

To analyze the outcome after surgery for critical limb ischemia (CLI) due to tibial artery occlusion in patients with systemic scleroderma. The medical records of scleroderma patients with CLI due to tibial artery occlusion were reviewed with respect to demographic data and perioperative variables. Eight patients were identified at The University of Tokyo Hospital from 1991 to 2007. The underlying collagen disease was progressive systemic scleroderma in 6 patients and CREST syndrome in 2 patients. The subjects were 1 man and 7 women with a mean age of 68 years. While hypercoagulability including positive anticardiolipin antibodies was found in only 1 patient, all patients were antinuclear antibody (ANA) positive and 6 of 8 patients had a high titer of centromere-type ANA. Five underwent pedal artery bypass and 1 underwent distal peroneal artery bypass, while 2 underwent primary limb amputation. Although 1 patient with bypass had early graft occlusion (with subsequent below-knee amputation), the other 5 patients with patent grafts quickly achieved pain relief and initial wound healing. However, four of the five patent grafts developed graft occlusion several months after surgery, with severe intimal thickening at the anastomosis. As a result, 2 of 6 patients with bypass (totally 4 of 8 patients) underwent limb loss and 1 patient developed persistent recurrent ulcer. Bypass surgery in patients with scleroderma and CLI can be successful in achieving early pain relief and ischemic wound healing. However, the long-term effectiveness is limited with high rates of graft failure and limb loss.

A new clinicopathological entity of IgG4-related inflammatory abdominal aortic aneurysm

Recently, the relationship between immunoglobulin (Ig)G4 and idiopathic sclerosing lesions has attracted much attention. IgG4-related disease was first described with regard to the pancreas (autoimmune pancreatitis), and has been expanded to various organ systems. We previously reported that inflammatory abdominal aortic aneurysm (IAAA) could be one of the manifestations of IgG4-related disease. In this study, we tried to elucidate the clinical characteristics of IgG4-related IAAA. This study consisted of 23 cases of IAAA and 40 cases of atherosclerotic abdominal aortic aneurysm (AAA). Clinical presentation, laboratory findings, and pathological features were examined. Aneurysms of 13 cases histologically corresponded to IgG4-related IAAA. Those cases accounted for 5% of all surgical AAAs, and 57% of IAAAs. Compared to non-IgG4-related IAAA, IgG4-related cases were characterized by less frequent association with abdominal or back pain. Serum IgG4 concentrations were significantly elevated in IgG4-related cases. Interestingly, patients with IgG4-related IAAA frequently showed an allergic constitution, such as drug allergy, autoimmune diseases, high serum IgE concentrations, and a high titer of antinuclear antibody. Pathologically, IgG4-related cases were characterized by more significant thickening of the adventitia and more numerous IgG4-positive plasma cell infiltrations. Three non-IgG4-related cases showed aneurysmal rupture at the time of first presentation, whereas no IgG4-related cases showed rupture. Recognizing a new disease entity of IgG4-related IAAA seems important because this was clinically and pathologically different from conventional aAAA and non-IgG4-related IAAA.

Presence of Autoimmune Antibody in Chikungunya Infection

Chikungunya infection has recently re-emerged as an important arthropod-borne disease in Thailand. Recently, Southern Thailand was identified as a potentially endemic area for the chikungunya virus. Here, we report a case of severe musculoskeletal complication, presenting with muscle weakness and swelling of the limbs. During the investigation to exclude autoimmune muscular inflammation, high titers of antinuclear antibody were detected. This is the report of autoimmunity detection associated with an arbovirus infection. The symptoms can mimic autoimmune polymyositis disease, and the condition requires close monitoring before deciding to embark upon prolonged specific treatment with immunomodulators.

A case of lupus nephritis coexisting with podocytic infolding associated with Takayasu’s arteritis

A 61-year-old Japanese woman with both Takayasu's arteritis (TA) and systemic lupus erythematosus (SLE) presented with proteinuria due to glomerulopathy associated with podocytic infolding. She presented with unequal pulses in the upper extremities at 38 years old. TA was diagnosed on the basis of angiographic identification of stenosis in the left subclavian artery. Eight years after onset of TA, SLE was diagnosed on the basis of clinical and laboratory findings, including proteinuria, hematological and immunological abnormalities, high titer of antinuclear antibody, and a positive lupus band test on the skin. A renal biopsy showed lupus nephritis coexisting with podocytic infolding associated with TA, which has rarely been reported. After low-dose prednisolone therapy and immunosuppressive therapy by cyclosporine for 14 years, proteinuria has persisted without deterioration of serum creatinine levels.

“ Borrelia-associated early-onset morphea”: A particular type of scleroderma in childhood and adolescence with high titer antinuclear antibodies? : Results of a cohort analysis and presentation of three cases

Morphea is an inflammatory autoimmune skin sclerosis of unknown etiology. A causative role of Borrelia burgdorferi infection has been controversially discussed, but no conclusive solution has yet been achieved. Intrigued by 3 young patients with severe Borrelia-associated morphea and high-titer antinuclear antibodies, we retrospectively examined the relationship between Borrelia exposure, serologic autoimmune phenomena and age at disease onset in morphea patients. In 90 morphea patients the presence of Borrelia-specific serum antibodies was correlated to the age at disease onset and the presence and titers of antinuclear antibodies. Patients with active Borrelia infection or high-titer antinuclear antibodies due to systemic sclerosis or lupus erythematosus served as controls. We observed a statistically highly significant association between morphea, serologic evidence of Borrelia infection, and high-titer antinuclear antibodies when disease onset was in childhood or adolescence. Because pathogenic Borrelia species may vary in different geographic regions the relevance of Borrelia infection in morphea induction may show regional variations. B burgdorferi infection may be relevant for the induction of a distinct autoimmune type of scleroderma; it may be called "Borrelia-associated early onset morphea" and is characterized by the combination of disease onset at younger age, infection with B burgdorferi, and evident autoimmune phenomena as reflected by high-titer antinuclear antibodies. As exemplified by the case reports, it may take a particularly severe course and require treatment of both infection and skin inflammation.

Antigen-specific responses and ANA production in B6. Sle1b mice: A role for SAP

B6. Sle1b mice, which contain the Sle1b gene interval derived from lupus prone NZM2410 mice on a C57BL/6 background, present with gender-biased, highly penetrant anti-nuclear antibody (ANA) production. To obtain some insight into the possible induction mechanism of autoantibodies in these mice we compared antigen-specific T dependent (TD) and T independent (TI-II) responses between B6. Sle1b and B6 mice before the development of high ANA titers. Our results show that B6. Sle1b mice mount enhanced responses to a TI-II antigen. Additionally, the memory T cell response generated by a TD antigen also increased. This enhancement correlates with the greater ability of B cells from B6. Sle1b mice to present antigen to T cells. The SLAM Associated Protein (SAP) is critical for signaling of many of the molecules encoded by the SLAM/CD2 gene cluster, candidates for mediating the Sle1b phenotype; therefore, we also investigated the effect of sap deletion in these strains on the TD and TI-II responses as well as on ANA production. The results of these studies of responses to non-self-antigens provide further insight into the mechanism by which responses to self-antigens might be initiated in the context of specific genetic alterations.

A case of adult-onset Satoyoshi syndrome with gastric ulceration and eosinophilic enteritis

The patient was misdiagnosed as having Sjögren's syndrome (on the basis of a lower-limb rash and dry eyes and mouth) in 1999, and then as having systemic lupus erythematosus (on the basis of hair loss and a high antinuclear antibody titer) in 2005. Total alopecia, muscular spasms and diarrhea developed over the following 2 years, and the patient experienced gastric ulceration in 2006. A rheumatologic opinion was sought in 2007. Physical examination, CBC, glucose tolerance test, iron studies, HLA typing, immunological investigations and complete gastrointestinal investigations, including gastroscopy, colonoscopy and small bowel biopsy. Satoyoshi syndrome with autoimmune features (high levels of antinuclear antibody and antibodies to thyroid tissue) and malabsorption due to eosinophilic enteritis. This patient is only the fifth adult in the world reported to have Satoyoshi syndrome, and the first-reported adult case from South Africa. The patient had only a transitory response to glucocorticoid treatment. Complete amelioration of symptoms resulted on two occasions when treated with intravenous immunoglobulin; however, the remissions only lasted for 6-8 weeks. More-intensive immunosuppression with azathioprine is currently being attempted.

Fine specificities of anti-nuclear antibodies in murine models of graft-versus-host disease

Two models of murine graft-versus-host disease (GVHD) were studied with respect to autoantibody production and development of systemic lupus erythematosus (SLE) like disease. One model was induced by injection of (B10.A(4R) x B10.A(2R]F1 mice with parental (B10.A(4R] spleen and lymph node cells (groups I GVHD), the other by injection of (DBA/2 x C57/B16)F1 mice with DBA/2 cells (group II GVHD). Group I GVHD mice remained in a seemingly healthy condition and did not show any proteinuria, in spite of high titres of anti-nuclear antibodies including antibodies to dsDNA, anti-Sm and anti-ribosomal P protein antibodies. Measured levels of these autoantibodies as well as their isotypes were comparable with those found in MRL/lpr and NZB/W mice. Group II GVHD mice developed SLE-like disease signs, including severe proteinuria. At 4 months after induction of the GVHD, almost 50% of these mice had died. At the time nephritis was present, group II mice also produced anti-dsDNA and anti-nuclear antibodies of other (unknown) specificities, but no anti-Sm or anti-P. Furthermore, the incidence of these antibodies was lower than observed in group I GVHD, MRL/lpr or NZB/W mice. It is concluded that (high avidity) anti-dsDNA as well as anti-Sm and anti-P may be present in the circulation without giving rise to the development of nephritis.

Fatal Autoimmune Hepatitis Induced by Concurrent Loss of Naturally Arising Regulatory T Cells and PD-1-Mediated Signaling

Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4(+)CD25(+) regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH. To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1(-/-) mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments. In contrast to NTx mice and PD-1(-/-) mice, NTx-PD-1(-/-) mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4(+) and CD8(+) T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1(-/-) mice was suppressed by transfer of Treg cells, even derived from PD-1(-/-) mice. Transfer of total but not CD4(+) T-cell-depleted splenocytes from NTx-PD-1(-/-) mice into RAG2(-/-) mice induced the development of severe hepatitis. In contrast, the transfer of CD8(+) T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma. NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.

Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies directed against various nuclear autoantigens, particularly against components of chromatin, such as doublestranded DNA (dsDNA), histones, nucleosomes, and ribonucleoproteins. Lupus nephritis, a severe clinical manifestation of SLE, is generally associated with high titers of antinuclear antibodies, especially antibodies against chromatin, and with immunoglobulin and complement deposits in the glomerulus. Historically, the formation of antibodies against dsDNA has been considered the serologic hallmark of SLE (1), and anti-dsDNA antibodies are found in the majority of SLE patients (2). In recent years, it has become clear that the nucleosome is the driving autoantigen in SLE (3), and some investigators claim that the presence of antinucleosome antibodies could serve as a better marker for SLE than anti-dsDNA antibodies, since the former are present in up to 90% of lupus patients (4,5). In SLE patients and in lupus-prone mice, nucleosomes can be found in the circulation; they are released from apoptotic cells and are present as a result of either disturbed apoptosis or a defective mechanism for clearing of apoptotic cells (3). Chromatin is basically defined as the entire complex of compacted DNA and associated proteins. The nucleosome is the fundamental unit of chromatin. The core nucleosome particle consists of 146 bp of dsDNA, wrapped twice around a histone octamer (2 copies of each of the core histones H2A, H2B, H3, and H4) (6). Antibodies against epitopes on the nucleosome, called nucleosome-specific antibodies, have no or very low reactivity against individual histones or naked dsDNA. The formation of nucleosome-specific antibodies precedes the appearance of anti-dsDNA and antihistone antibodies as a result of epitope spreading. Anti-dsDNA and antihistone antibodies bind to dsDNA and histones, respectively, but also to nucleosomes (7). A serious topic of debate for several decades involves the pathogenicity, and especially the nephritogenicity, of anti-dsDNA antibodies. DNA itself is not immunogenic, and immunization of mice with naked dsDNA leads to rapid removal, mainly through the liver. Nevertheless, anti-dsDNA antibody levels often show a high correlation with disease activity, especially in lupus nephritis, and elucidating their pathogenic properties is thus of great interest. Therefore, the targets of antidsDNA antibodies have been intensively studied to gain clues to mechanisms that could explain the pathogenicity of anti-dsDNA antibodies in SLE. With regard to their role in the development of lupus nephritis, many investigators postulate that antidsDNA antibodies localize in the glomerular basement membrane (GBM) due to direct cross-reactive binding to intrinsic glomerular antigens (mechanism 1), whereas, in our opinion, glomerular localization of anti-dsDNA antibodies is mediated via nucleosomes, which bind to heparan sulfate (HS) in the GBM (mechanism 2). These two hypotheses may not be mutually exclusive, and until recently, there was no unequivocal proof for either of the two proposed mechanisms. In this review, we will discuss the pros and cons of each of these mechanisms, taking into account recent pertinent observations by Supported by the Dutch Kidney Foundation (grant C05.2119), the PhD student program of the Radboud University Nijmegen Medical Centre, the Health and Rehabilitation Organization, Norway (grant 2001/2/0235), and Oslo Sanitetsforening and Skibsreder Tom Wilhelmsens Stiftelse. Casandra C. van Bavel, MSc, Johan van der Vlag, PhD, Jo H. Berden, MD, PhD: Nijmegen Centre for Molecular Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Kristin A. Fenton, PhD: University of Tromso, Tromso, Norway; Ole P. Rekvig, MD, PhD: University of Tromso, and University Hospital of North Norway, Tromso, Norway. Address correspondence and reprint requests to Jo H. Berden, MD, PhD, Division of Nephrology (464), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: J.Berden@nier.umcn.nl. Submitted for publication November 8, 2007; accepted in revised form April 14, 2008.

Severe Systemic Lupus Erythematosus Induced by Antiviral Treatment for Hepatitis C

We report the case of a 43-year-old man who developed systemic lupus erythematosus (SLE) after receiving pegylated alpha-interferon and ribavirin for chronic hepatitis C. He displayed 8 features of the American College of Rheumatology criteria for SLE: glomerulonephritis, arthritis, serositis, a florid discoid rash, lymphopenia, oral ulcers, the development of high titers of antinuclear antibodies, and antidouble stranded DNA antibodies. Furthermore, his admission was complicated by the development of life threatening myopericarditis and vasculitis. This case is notable for the clinical severity and nature of multiorgan lupus involvement from hepatitis C antiviral therapy. Clinical signs of SLE have resolved and anti DS DNA has normalized.

Outcome of high titer antinuclear antibody positivity in individuals without connective tissue disease: a 10-year follow-up

To ascertain the development of disease in a cohort of connective tissue disease (CTD)-negative patients 10 years after testing positive for antinuclear antibody (ANA) in high titer, a telephone survey and serological tests were conducted on a group of CTD-negative patients with high ANA titer identified in a previous study. Thirty-four out of 62 patients (55%) completed only the telephone survey and 27 completed both. The mean length of follow-up was 11.5 years. The ages ranged from 27 to 89 years with the mean being 58.9 years. The sex distribution included 4 (12%) men and 30 (88%) women. Twenty-one out of 27 patients (78%) remained ANA-positive. A total of five patients were diagnosed with CTD with two in the last 5 years. Common symptoms described, in order of frequency, were joint pain, Raynaud's phenomenon, and Sicca symptoms. This study shows that a considerable percentage of CTD-negative individuals with an initial high ANA titer continue to maintain their positivity even after an extended period. It is reassuring, however, that only a small number of these individuals go on to develop CTD. It confirms the fact that the ANA test, despite remaining a useful clinical tool, needs to be used in conjunction with other evidence and clinical judgement when attempting to validate the diagnosis of CTD.

Type B insulin resistance syndrome induced by increased activity of systemic lupus erythematosus in a hemodialysis patient

A-23-year-old woman with systemic lupus erythematosus (SLE) and on hemodialysis for 5 years was admitted to the hospital because of severe general fatigue. On admission, laboratory findings showed that fasting plasma glucose levels ranged from 25 â 45 mg/dl, a test for antinuclear antibody (ANA) was positive (1 : 320, with a discrete-speckled pattern), serum C3 and C4 complement and CH50 level were remarkably depressed (22.5 mg/dl, < 5.1 mg/dl, < 13 U/ml, respectively), and insulin receptor antibodies were present (89.3% inhibition of 125I-insulin binding to cultured human lymphocytes by a binding inhibition assay). She also showed acanthosis nigricans. The patient was diagnosed to suffer from a Type B insulin resistance syndrome. The patient's serum insulin and C-peptide levels were markedly elevated during hypoglycemia without insulinoma (2,313.8 microU/ml, 55 ng/ml, respectively). Interestingly, not only postprandial hyperglycemia but also fasting hypoglycemia was observed. Treatment with steroid pulse and subsequent high dose of prednisolone resulted in restoration of euglycemia associated with disappearance of insulin receptor antibodies and improvement of both serum hypocomplementemia and the high titer of ANA. Later, the patient's course was complicated by hemorrhagic shock due to duodenal ulcer and she died of subsequent pneumocystis carinii pneumonia. The presented patient developed a Type B insulin resistance syndrome induced by increased activity of SLE after she had been treated with hemodialysis for 5 years. This is the first reported case with such a history and constellation. It is recommended that SLE patients on dialysis are carefully followed-up by clinical and serological monitoring. Type B insulin resistance syndrome must be considered in the differential diagnosis of hypoglycemia in SLE patients on dialysis.

Intramembranous electron-dense deposits in a nephrotic patient with mixed connective tissue disease: unusual response to corticosteroid therapy.

A 56-year-old female patient, who had had minor change nephrotic syndrome (MCNS), was referred to us because of a fever and a massive proteinuria. Six years before, she had first noticed leg oedema, leading to the detection of nephrotic-range proteinuria. The diagnosis of MCNS at that time was based on minor glomerular abnormality by the light microscopy examination. She had then been treated with corticosteroid, after which her proteinuria had promptly disappeared. Her corticosteroid had then been gradually withdrawn, and no relapse had occurred for 6 years. At her first visit with us, she had a fever and sclerodactylia as well as swollen hands and Raynaud’s phenomenon, and laboratory examinations showed a high titer of anti-nuclear and anti-RNP antibodies, resulting in a diagnosis of mixed connective tissue disease (MCTD). She also had a massive proteinuria (3.2 g/day), and a kidney re-biopsy was performed (Figure 1). She was treated again with corticosteroid (prednisolone 20 mg daily) and her proteinuria had completely disappeared within a week.