Search

Place: France; Devic neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associating acute transverse myelitis and optic neuritis. This is a different disease from multiple sclerosis for which the presence of the NMO antibody directed against aquaporin 4 is a specific marker. Brain damage on MRI does not exclude the diagnosis; the location is superposable in the brain zones rich in aquaporin 4 channels. We report 2 cases of NMO with anti-aquaporin 4. One patient was not symptomatic of brain damage. In this patient, the affinity of anti-NMO for aquaporin 4, studied by flow cytometry, was particularly high. Both patients were treated with immunosuppressive agents (rituximab) due to the failure of or dependence on high-dose corticosteroids.

The aim of this study was to investigate the relationship between insulin resistance and thyroid function in obese pre- and postmenopausal women with or without metabolic syndrome (MetS). 141 obese women were divided into two groups, HOMA-IR2.7, to evaluate relation with HOMA-IR and fatness, hormone and blood parameters. They were then divided into four groups as pre- and postmenopausal with or without MetS. Various fatness, hormone and blood parameters were examined. Statistically significant difference was found in weight, body mass index (BMI), waist circumference, fat%, fasting insulin, TSH, FT3, FT4, FSH, Anti-microsomal antibody (ANTIM) and triglycerides levels in HOMA-IR2.7 obese Turkish women. This study showed that age, weight, BMI, waist circumference, fat%, fasting insulin, FT3, ANTIM, FSH, LH, total cholesterol, triglycerides, HDL, HOMA-IR, systolic and diastolic blood pressure levels were related in preand post menopausal status in obese women with or without MetS. Obesity may influence the levels of thyroid hormones and increases the risk of MetS in women. Postmenopausal status with MetS is associated with an increased TSH, FT3 and FT4 levels and HOMA-IR in obese women. Strong relation was observed with MetS and TSH and FT3 levels. ©2012, Editrice Kurtis.

We aimed at determining whether anti-apolipoprotein (apo) A-1 IgG levels are independent predictors of coronary artery calcification (CAC) and coronary endothelial dysfunction in obese and nonobese subjects without cardiovascular disease. 48 nonobese and 43 obese subjects were included. CAC score was measured by thorax scanner and defined by an Agatston score > 0. Coronary endothelial dysfunction was determined by measuring myocardial blood flow responses to cold pressor test (CPT) on PET/CT. Serum anti-apoA-1 IgG levels were measured by ELISA. Prevalence of coronary calcification was similar between the two study groups, but the prevalence of coronary endothelial dysfunction was higher in obese subjects. Anti-apoA-1 IgG levels and positivity rate were higher in obese than in nonobese individuals. CAC score was higher in anti-apoA-1 IgG positive subjects. ROC analyses indicated that anti-apoA-1 IgG levels were significant predictors of CAC > 0, but not of coronary endothelial dysfunction with a negative predictive value of 94%. Anti-apoA-1 IgG positivity was associated with a 17-fold independent increased risk of CAC > 0. In conclusion, those preliminary results indicate that anti-apoA-1 IgG autoantibodies are raised in obese subjects and independently predict the presence of coronary calcification in this population but not the presence of coronary endothelial dysfunction.

Keller P F Pagano S Roux Lombard P Sigaud P Rutschmann OT Mach F Hochstrasser D Vuilleumier N (Geneva University Hospitals Geneva). Autoantibodies against apolipoprotein A 1 and phosphorylcholine for diagnosis of non ST segment elevation myocardial infarction. J Intern Med 2011; doi: 10.1111/j.1365 2796.2011.02479.x Objectives. To explore the diagnostic accuracies of anti apolipoproteinA 1 (anti ApoA 1) IgG and anti phosphorylcholine (anti PC) IgM alone expressed as a ratio (anti ApoA 1 IgG/anti PC IgM) and combined with the Thrombolysis In Myocardial Infarction (TIMI) score for non ST segment elevation myocardial infarction (NSTEMI) (NSTEMI TIMI score) to create a new diagnostic algorithm the Clinical Autoantibody Ratio (CABR) score for the diagnosis of NSTEMI and subsequent cardiac troponin I (cTnI) elevation in patients with acute chest pain (ACP). Methods. In this single centre prospective study 138 patients presented at the emergency department with ACP without ST segment elevation myocardial infarction. Anti ApoA 1 IgG and anti PC IgM were assessed by enzyme linked immunosorbent assay on admission. Post hoc determination of the CABR score cut off was performed by receiver operating characteristics analyses. Results. The adjudicated final diagnosis was NSTEMI in 17 (24/138) of patients. Both autoantibodies alone were found to be significant predictors of NSTEMI diagnosis but the CABR score had the best diagnostic accuracy [area under the curve (AUC): 0.88; 95 confidence interval (CI): 0.82 0.95]. At the optimal cut off of 3.3 the CABR score negative predictive value (NPV) was 97 (95 CI: 90 99). Logistic regression analysis showed that a CABR score >3.3 increased the risk of subsequent NSTEMI diagnosis 19 fold (odds ratio: 18.7; 95 CI: 5.2 67.3). For subsequent cTnI positivity only anti ApoA 1 IgG and CABR score displayed adequate predictive accuracies with AUCs of 0.80 (95 CI: 0.68 0.91) and 0.82 (95 CI: 0.70 0.94) respectively; the NPVs were 95 (95 CI: 90 98) and 99 (95 CI: 94 100) respectively. Conclusion. The CABR score derived from adding the anti ApoA 1 IgG/anti PC IgM ratio to the NSTEMI TIMI score could be a useful measure to rule out NSTEMI in patients presenting with ACP at the emergency department without electrocardiographic changes.

OBJECTIVES: Thyroid dysfunction in the setting of systemic sclerosis (SSc) has been described previously. We aimed to determine the prevalence of anti-thyroid antibodies (ATA) in a large SSc cohort and to ascertain whether they are associated with distinct clinical phenotypes. METHODS: A total of 138 patients with SSc [46 with diffuse (dSSc) and 92 with limited scleroderma (lSSc)] and 100 healthy controls (HC) were tested for the presence of ATA [anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibodies] using a commercial enzyme-linked immunosorbent assay (ELISA). Clinical and serological data were recorded. RESULTS: An increased prevalence of anti-TPO but not anti-Tg antibodies was detected in patients with SSc compared to HC (27.5% vs. 14%, p = 0.016). Of note, a statistically significant increase of anti-TPO was detected only in patients with lSSc compared to HC (32.6% vs. 14%, p = 0.003). No correlations with other clinical features were detected. CONCLUSIONS: An increased prevalence of anti-TPO antibodies was identified in patients with lSSc. We propose that ATA testing should be offered to this subgroup of patients. Scandinavian Journal of Rheumatology

Item does not contain fulltext OBJECTIVE: To assess the 6-month effectiveness of the first rituximab (RTX) course in rheumatoid arthritis (RA) and to identify possible predictors of response. METHOD: 10 European registries submitted anonymised datasets (baseline, 3- and 6-month follow-up) from patients with RA who had started RTX, and datasets were pooled and analysed. Heterogeneity between countries was analysed by analysis of variance. Predictors of response were identified by logistic regression. RESULTS: 2019 patients were included (mean age/disease duration 53.8/12.1 years, 80.3% female, 85.6% rheumatoid factor (RF) positive and 76.8% (456/594 patients) anti-cyclic citrullinated peptide antibodies (anti-CCP) positive). For these patients an average of 2.7 disease-modifying antirheumatic drugs (DMARDs) (range 0-10) had failed, and RTX was given as the first biological agent in 36.6% of patients. There was significant heterogeneity between countries for several baseline characteristics, including the number of previous biological agents. Disease Activity Score based on 28 joint counts (DAS28) decreased from 5.8+/-1.4 at baseline to 4.2+/-1.4 at 6 months (p

OBJECTIVE: RA is associated with premature atherosclerosis. Here, we determined the associations of apolipoproteins and immunoglobulin M (IgM) antibodies against phosphorylcholine (anti-PC) with carotid artery atherosclerosis in a prospective cohort of patients with early RA. METHODS: In all 114 patients, age 50.6 (11.2) years, 68.4% women, with recent RA (

Biomarkers of clinical relevance are very important in the workup of patients presenting with neurological autoimmune diseases. Nervous biopsy remains often the "gold standard procedure" but is limited in practice due to the risk of complication and insufficient yield. These biomarkers, most often auto-antibodies, can be the direct cause of the neurological syndrome or be detected as an epiphenomenon of the pathogenic process. The detection of these biomarkers, when performed in well defined clinical conditions, may help the clinician to establish a definite diagnosis which may in turn facilitate the therapeutic decision. The purpose of this article is to review the biomarkers that are available in daily practice to investigate immune-mediated neurological conditions.

Perinuclear antineutrophil cytoplasmic antibodies have recently been demonstrated in the sera of patients with inflammatory bowel disease. Three hundred and sixty six sera obtained from 120 patients with ulcerative colitis, 105 patients suffering from Crohn's disease and 49 non-inflammatory bowel disease controls were tested in two laboratories, using an indirect immunofluorescence assay. In addition, a fixed-neutrophil enzyme linked immunoadsorbent assay (ELISA) was evaluated in one of the two laboratories. The results in the immunofluorescence test showed a high degree of correlation between the two laboratories (Kappa coefficient = 0.8). Ninety five of the 120 (79%) ulcerative colitis patients had a positive test whereas only 14 of the 105 (13%) patients with Crohn's disease were positive. Sera from four patients suffering from primary sclerosing cholangitis were positive as well as four of the 45 control sera (9%). The sensitivity of the perinuclear antineutrophil cytoplasmic antibody immunofluorescence test for the diagnosis of ulcerative colitis was 0.75 with a specificity of 0.88 and a positive predictive value of 0.88 (all sera). In the ELISA technique 37 of 94 ulcerative colitis sera and one of the 68 Crohn's disease sera were positive. In the control group only one of the patients suffering from primary sclerosing cholangitis reacted positively (32 non-inflammatory bowel disease sera tested). The ELISA technique had a high specificity (0.97), but a low sensitivity (0.39). There was no relation of perinuclear antineutrophil cytoplasmic antibodies in ulcerative colitis patients or in Crohn's disease patients with disease activity, duration of illness, localisation, extent of disease, previous bowel operations or medical treatment. The clinical significance of perinuclear antineutrophil cytoplasmic antibody positive and negative subsets in both groups of patients thus remains unexplained. Our study confirms that determination of serum antineutrophil cytoplasmatic antibodies in patients with inflammatory bowel disease may differentiate ulcerative colitis from Crohn's disease. Further immunological studies are needed to explain the absence of these antibodies in a subset of ulcerative colitis patients and their role in the pathogenesis of the disease.

Our goals were to study the proposed association of IL-2RA /CD25 with type 1 diabetes in the Belgian population over a broad age range, and to explore possible correlations with disease phenotypes, immune markers, HLA-DQ, INS, and PTPN22. Patients (n = 1954), healthy controls (n = 2082), and families (n = 420) were genotyped for IL-2RA/CD25 rs41295061(C>A), HLA-DQ, INS-VNTR and PTPN22. IL-2RA/CD25 was associated with type 1 diabetes (χ(2) = 26.8, p < 0.001 for alleles and χ(2) = 29.6, p < 0.001 for genotypes). The C allele (odds ratios [OR] = 1.59) and C/C genotype (OR = 1.56) were identified as susceptibility variants, whereas the A allele (OR = 0.63), A/A genotype (OR = 0.14), and A/C genotype (OR = 0.69) as protective variants. IL-2RA/CD25 is associated with both early-onset and late-onset type 1 diabetes, but with a larger effect size in early-onset disease. There was a nonsignificant tendency toward transmission distortion (p = 0.063). Except a tendency toward younger age at onset in carriers of the C/C genotype, no correlations with disease phenotype, immune markers, HLA-DQ, INS and PTPN22 were observed. Also, the frequency of the susceptible genotype was higher in early-onset compared with late-onset TID patients (p = 0.015). In conclusion, IL-2RA/CD25 is associated with type 1 diabetes in the Belgian population, independently of disease phenotype and other biologic markers.

Miller Fisher syndrome (MFS) is an autoimmune neuropathy characterized by external ophthalmoplegia, ataxia and areflexia. Mydriasis is present in 35% of typical MFS. We report five patients with acute bilateral mydriasis, either isolated or associated with external ophthalmoplegia for which the presumed diagnosis of "atypical MFS" was confirmed by the positivity of anti-GQ1b antibodies. Acute bilateral mydriasis raises important differential diagnoses in clinical practice. This report demonstrates that acute mydriasis can be autoimmune mediated and that anti-GQ1b antibodies are useful to confirm the diagnosis in unexplained cases.

AIM: We report four cases of acquired severe encephalopathy with massive hyperkinesia, marked neurological and cognitive regression, sleep disturbance, prolonged mutism, and a remarkably delayed recovery (time to full recovery between 5 and 18mo) with an overall good outcome, and its association with anti-N-methyl-d-aspartate (anti-NMDA) receptor antibodies. METHOD: We reviewed the four cases retrospectively and we also reviewed the literature. RESULTS: Anti-NMDA receptor antibodies (without ovarian teratoma detected so far) were found in the two children tested in this study. INTERPRETATION: The clinical features are similar to those first reported in 1992 by Sebire et al.,(1) and rarely recognized since. Sleep disturbance was not emphasized as part of the disorder, but appears to be an important feature, whereas coma is less certain and difficult to evaluate in this setting. The combination of symptoms, evolution (mainly seizures at onset), severity, paucity of abnormal laboratory findings, very slow recovery, and difficult management justify its recognition as a specific entity. The neuropathological substrate may be anatomically close to that involved in encephalitis lethargica, in which the same target functions (sleep and movement) are affected but in reverse, with hypersomnolence and bradykinesia. This syndrome closely resembles anti-NMDA receptor encephalitis, which has been reported in adults and is often paraneoplastic.

BACKGROUND:The main processes in the pathogenesis of cerebral malaria caused by Plasmodium falciparum involved sequestration of parasitized red blood cells and immunopathological responses. Among immune factors, IgG autoantibodies to brain antigens are increased in P. falciparum infected patients and correlate with disease severity in African children. Nevertheless, their role in the pathophysiology of cerebral malaria (CM) is not fully defined. We extended our analysis to an Indian population with genetic backgrounds and endemic and environmental status different from Africa to determine if these autoantibodies could be either a biomarker or a risk factor of developing CM. METHODS/PRINCIPAL FINDINGS:We investigated the significance of these self-reactive antibodies in clinically well-defined groups of P. falciparum infected patients manifesting mild malaria (MM), severe non-cerebral malaria (SM), or cerebral malaria (CM) and in control subjects from Gondia, a malaria epidemic site in central India using quantitative immunoprinting and multivariate statistical analyses. A two-fold complete-linkage hierarchical clustering allows classifying the different patient groups and to distinguish the CM from the others on the basis of their profile of IgG reactivity to brain proteins defined by PANAMA Blot. We identified beta tubulin III (TBB3) as a novel discriminant brain antigen in the prevalence of CM. In addition, circulating IgG from CM patients highly react with recombinant TBB3. Overall, correspondence analyses based on singular value decomposition show a strong correlation between IgG anti-TBB3 and elevated concentration of cluster-II cytokine (IFNgamma, IL1beta, TNFalpha, TGFbeta) previously demonstrated to be a predictor of CM in the same population. CONCLUSIONS/SIGNIFICANCE:Collectively, these findings validate the relationship between antibody response to brain induced by P. falciparum infection and plasma cytokine patterns with clinical outcome of malaria. They also provide significant insight into the immune mechanisms associated to CM by the identification of TBB3 as a new disease-specific marker and potential therapeutic target.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by B cell hyperactivity leading to the production of various autoantibodies and subsequent development of glomerulonephritis, i.e. lupus nephritis. Among the principal targets of autoantibodies produced in murine SLE are nucleic acid-protein complexes, such as chromatin and ribonucleoproteins, and the envelope glycoprotein gp70 of endogenous retroviruses. The preferential production of these autoantibodies is apparently promoted by the presence of genetic abnormalities leading to defects in the elimination of apoptotic cells and to an enhanced expression of endogenous retroviruses. Moreover, recent studies revealed that the innate receptors TLR7 and TLR9 are critically involved in the activation of dendritic cells and autoreactive B cells through the recognition of endogenous DNA- or RNA-containing antigens and subsequent development of autoimmune responses against nuclear autoantigens. Furthermore, the regulation of autoimmune responses against endogenous retroviral gp70 by TLR7 suggested the implication of endogenous retroviruses in this autoimmune response. Clearly, further elucidation of the precise molecular role of TLR7 and TLR9 in the development of autoimmune responses will help to develop novel therapeutic strategies and targets for SLE.

Background. One year survival of islet cell grafts has been reproducibly achieved under combination immune therapy including tacrolimus (TAC). However, the use of TAC causes beta-cell and renal toxicity. Because sirolimus (SIR) monotherapy was successful in kidney transplantation under antithymocyte globulin (ATG), we undertook a pilot study comparing SIR monotherapy with SIR-TAC combination therapy. Methods. Nonuremic type 1 diabetics received a cultured beta-cell graft under ATG and were randomly assigned to SIR or SIR-TAC-maintenance therapy; a second graft was implanted during posttransplantation month 3 without ATG. The planned number of patients per group (n= 10) was reduced to five in view of the observed side effects. Results. At posttransplant month 6, three SIR-patients had lost graft function and two presented marginal function; among SIR-TAC-patients, there were two early graft failures but three became insulin-independent. These three patients maintained metabolically relevant function (C-peptide > 1 ng/ml and coefficient of variation fasting glycemia

OBJECTIVE: Previous studies have revealed the presence of IgG antifibroblast antibodies (AFAs) capable of binding to the surface of fibroblasts in systemic sclerosis (SSc) sera. Since chemokines may directly or indirectly affect the development of fibrosis, this study was undertaken to investigate the production of chemokines induced by AFAs in fibroblasts, and to characterize the signaling pathways and surface molecules involved. METHODS: AFA-positive and AFA-negative IgG were tested on fibroblasts. Chemokine messenger RNA expression was screened by microarray and quantitative reverse transcription-polymerase chain reaction. Production of CCL2, CXCL8, and CXCL10 proteins was assessed by enzyme-linked immunosorbent assay. Pharmacologic inhibitors were used to study signal transduction, with results assessed by Western blotting and immunofluorescence analysis. Fibroblasts with defective expression of Toll-like receptors (TLRs) and anti-TLR monoclonal antibodies (mAb) were used to assess AFA specificity. RESULTS: In human fibroblasts, AFA-positive IgG induced the preferential transcription of chemokines with profibrotic and proangiogenic potential, including, but not exclusively, CCL2, CXCL1, CXCL8, CKLF, and ECGF1, which were distinctly different from those induced by interferon-gamma. Levels of CCL2 and CXCL8 proteins were increased in AFA-stimulated fibroblast culture supernatants. AFA binding to fibroblasts resulted in concomitant activation of ERK-1/2, c-Jun, and NF-kappaB. CCL2 production was sensitive to inhibition of both proteasome and JNK, while CXCL8 production was sensitive only to inhibition of proteasome. AFAs failed to up-regulate CCL2 expression in TLR-4-deficient fibroblasts but not in TLR-6- or TLR-2-deficient fibroblasts. Moreover, anti-TLR-4 mAb, but not anti-TLR-2 mAb, partially inhibited the production of CCL2 induced by AFAs in human fibroblasts. CONCLUSION: Autoantibodies that bind to the surface of fibroblasts may contribute to the pathogenesis of SSc by up-regulating the fibroblast production of profibrotic and proangiogenic chemokines, in a proteasome- and TLR-4-dependent manner.

ApoA-1 (apolipoprotein A-1) is the main component of HDL (high-density lipoprotein) and stabilizes PON-1 (paraoxonase-1), which prevents lipid peroxidation and oxLDL (oxidized low-density lipoprotein) formation. Autoantibodies against apoA-1 [anti-(apoA-1) IgG] have been found in antiphospholipid syndrome and systemic lupus erythematosous, two diseases with an increased risk of thrombotic events, as well as in ACS (acute coronary syndrome). OxLDL levels are also elevated in these diseases. Whether anti-(apoA-1) IgGs exist in other prothrombotic conditions, such as APE (acute pulmonary embolism) and stroke, has not been studied and their potential association with oxLDL and PON-1 activity is not known. In the present study, we determined prospectively the prevalence of anti-(apoA-1) IgG in patients with ACS (n=127), APE (n=58) and stroke (n=34), and, when present, we tested their association with oxLDL levels. The prevalance of anti-(apoA-1) IgG was 11% in the ACS group, 2% in the control group and 0% in the APE and stroke groups. The ACS group had significantly higher median anti-(apoA-1) IgG titres than the other groups of patients. Patients with ACS positive for anti-(apoA-1) IgG had significantly higher median oxLDL values than those who tested negative (226.5 compared with 47.7 units/l; P

Background: Systemic sclerosis (SSc) is a multisystem autoimmune disease which is classified into a diffuse cutaneous (dcSSc) and a limited cutaneous (lcSSc) subset according to the skin involvement. In order to better understand the vascular, immunological and fibrotic processes of SSc and to guide its treatment the EULAR Scleroderma Trials And Research (EUSTAR) group was formed in June 2004. Aims and Methods: EUSTAR collects prospectively the Minimal Essential Data Set (MEDS) on all sequential patients fulfilling the ACR diagnostic criteria in participating centres. We aimed to characterize demographic, clinical and laboratory characteristics of disease presentation in SSc and analysed EUSTAR baseline visits. Results: In April 2006, a total of 3656 patients (1349 with dcSSc and 2101 with lcSSc) were enrolled in 102 centres and 30 countries. 1330 individuals had autoantibodies against Scl70 and 1106 against anticentromere antibodies. 87% of patients were female. On multivariate analysis, scleroderma subsets (dcSSc vs. lcSSc), antibody status and age at onset of Raynaud’s phenomenon, but not gender were independently associated with the prevalence of organ manifestations. Autoantibody status in this analysis appeared more closely associated with clinical manifestations than were SSc subsets. Conclusion: dcSSc and lcSSc subsets are associated with particular organ manifestations, but in this analysis the clinical distinction appeared superseded by an antibody based classification in predicting some scleroderma complications. The EUSTAR MEDS data base facilitates the analysis of clinical patterns in SSc and contributes to the standardised assessment and monitoring of SSc internationally.

BACKGROUND/AIMS: The aim of this study was to investigate the possible role of interferon-alpha in the development of antiplatelet IgG antibodies in patients with chronic viral hepatitis B or C. METHODOLOGY: Ninety-one consecutive patients with chronic viral hepatitis (51 with chronic hepatitis B and 40 with chronic hepatitis C) were investigated for the presence of antiplatelet IgG antibodies in their serum immediately prior to IFN-alpha therapy and after six months of therapy. The method used was the solid phase red cell adherence test (Immucor, Norcross, USA), which is a sensitive tracer of antiplatelet antibodies. Some of the results were confirmed using an indirect immunofluorescence test for the detection of antiplatelet antibodies RESULTS: Overall, we found that antiplatelet antibodies were present in 37.54% (19/51) of patients with chronic hepatitis B before IFN-alpha therapy and in 35.29% (18/51) after therapy. Moreover, antiplatelet antibodies were found in 20% (8/40) of patients with chronic hepatitis C before and after IFN-alpha therapy. CONCLUSIONS: Therapy with IFN-alpha did not induce antiplatelet antibodies in patients with chronic viral hepatitis B or C. Thrombocytopenia observed during IFN-alpha therapy in our study was not due to the development of antiplatelet antibodies. Hepatogastroenterology

BACKGROUND: Anti-C1q antibodies (anti-C1q) have been shown to correlate positively with systemic lupus erythematosus (SLE) nephritis. Several clinical studies indicated a high negative predictive value, suggesting that active lupus nephritis is rarely seen in patients with no anti-C1q. However, the true prevalence of anti-C1q at the time of active lupus nephritis has not been well established. The aim of this study was to determine prospectively the prevalence of anti-C1q in proven active lupus nephritis at the time of the renal biopsy. METHODS: In this prospective multi-centre study, we investigated adult SLE patients undergoing renal biopsy for suspected active lupus nephritis. Serum samples were taken at the time of the biopsy and analysed for the presence of anti-C1q in a standardized way. The activity of lupus nephritis was classified according to the renal histology. Biopsies were also analysed for the presence of glomerular IgG, C1q and C3 deposition. RESULTS: A total of 38 patients fulfilling at least 4/11 American College of Rheumatology (ACR) criteria for the diagnosis of SLE were included. Out of this, 36 patients had proliferative (class II, III or IV) and two had class V lupus nephritis. All but one patient with proliferative lupus nephritis were positive for anti-C1q (97.2%) compared with the 35% of control SLE patients with inactive lupus nephritis and 25% of SLE patients without lupus nephritis ever. All patients were positive for glomerular C1q (36/36) and 37/38 patients had glomerular IgG deposits. Anti-C1q strongly decreased during successful treatment. CONCLUSIONS: Anti-C1q have a very high prevalence in biopsy-proven active lupus nephritis, thus a negative test result almost excludes active nephritis. The data support the hypothesis of a pathogenic role of anti-C1q in lupus nephritis.

The heterozygous combination of DQA1*03-DQB1*0302 (DQ8) and DQA1*05-DQB1*0201 (DQ2) confers the highest known HLA-DQ-linked risk for type 1 diabetes, suggesting a role for transcomplementation. The trans -heterodimer encoded by DQA1*03 and DQB1*02 is also rarely observed in cis in whites. Islet antibody–positive diabetic patients (P; n = 2238) and control subjects (C; n = 2223) of white descent were genotyped by a HLA-DQA1-DQB1 dot-blot method. The presence of the DQA1*03-DQB1*02 haplotype was observed in 22 patients (1%) versus 6 controls (0.3%) (odds ratio [OR] = 3.7, p = 0.005). It was more prevalent in whites of Northern African descent, but both in European ( n = 3813) and in Northern African whites ( n = 648), the DQA1*03-DQB1*02 haplotype tended to be associated with diabetes (respectively, P 0.3% vs. C 0.03%, OR = 12.2, p = 0.005; and P 2.1% vs. C 0.6%, OR = 3.8, p = 0.03). DRB1 typing revealed that DQA1*03-DQB1*02 is usually associated with the DRB1*0405 risk allele in European patients and with DRB1*0405, DRB1*07 and DRB1*09 in Northern African whites. Like in DQ2/DQ8-positive patients, the presence of DQA1*03-DQB1*02 is preferentially associated with younger age at clinical onset than in other genotypes, but unlike in subjects carrying DQ2/DQ8, earlier clinical manifestation was mostly restricted to male subjects, often carrying DR3 and/or DQB1*02 on the other chromosome. These results are compatible with an effect of cis -encoded heterodimers or with previously suggested interactions of X-linked genetic factors with (DR3-)DQB1*02 haplotypes.

Background: Bile duct injury is not a feature of classical autoimmune hepatitis (AIH), but it has been described in variant forms of the disease. Aims: Our goals were to assess the similarity of AIH with bile duct injury to classical disease and to evaluate the possibility of concurrent primary biliary cirrhosis (PBC). Methods: Fifteen patients with bile duct injury were compared with 151 patients with classical AIH. Patterns of nuclear immunofluorescence and the frequency and nature of autoantibodies associated with AIH and PBC were determined. Results: Patients with bile duct injury had the same nuclear-staining patterns, frequency and nature of autoantibodies, and genetic risk factors as the comparison group. Features specific for PBC, including the multiple nuclear dot pattern of immunofluorescence and antibodies to the M2 antigens, Sp100 and nuclear pore complex antigen, gp210, did not distinguish them from classical disease. Remission and treatment failure occurred with similar frequencies in both groups. Conclusions: Patients with AIH and bile duct injury lack features of PBC, and they respond as well to corticosteroid therapy as patients with classical disease. Background bile duct changes should not alter the diagnosis or treatment of AIH.

The current iodine status and the impact of silent iodine prophylaxis on the prevalence of autoimmune thyroiditis among schoolchildren in a formerly iodine-deficient community in northwestern Greece, were investigated. The findings were compared to those obtained from a similar survey conducted 7 years previously in the same area. A total of 302 schoolchildren (12-18 years of age) from a mountainous area of northwestern Greece were examined for the presence of goiter, and blood and urine samples were collected for assessment of thyroid function, antithyroid antibodies and urinary iodine excretion. In those children (n = 42) with palpable goiter or positive antibodies and/or a thyrotropin (TSH) level greater than 5 mU/L, thyroid ultrasonography was performed to estimate thyroid gland size and morphology. Median urinary iodine concentration in the children was 20.21 microg/dL, indicating sufficient iodine intake. Thyroid function was normal in all but 7 children, who had subclinical hypothyroidism (2.5%). Antithyroid antibodies (antithyroid peroxidase [TPO] and/or antithyroglobulin [Tg]) were positive in 32 children, including those with subclinical hypothyroidism (10.6%). Twenty-nine of these children (9.6%) also had the characteristic echo pattern of thyroiditis on ultrasound and were diagnosed to have autoimmune thyroiditis. In comparison to data from our previous survey 7 years ago, there has been a threefold increase in the prevalence of autoimmune thyroiditis among schoolchildren. In conclusion, silent iodine prophylaxis has resulted in the elimination of iodine deficiency in Greece, and this has been accompanied by an increase in the prevalence of autoimmune thyroiditis. Thyroid

Pure white cell aplasia (PWCA) is a rare disorder of unknown origin, often associated with thymoma, characterized by selective neutropenia or pure agranulocytosis, and absence of granulocyte precursors in the bone marrow, but with normal erythroblasts and megakaryocytes. We report a case of PWCA associated with thymoma. Unusual findings in this case report included simultaneous presence of autoimmune thyroiditis, type 1 diabetes, anti-striated muscle antibodies, and the presence in the peripheral blood of CD8+ T cells that expressed a homogeneous naive phenotype. Neutrophil count became normal on immunosuppressive therapy after thymectomy.

BACKGROUND: Although controversial, some authorities have implicated hepatitis C virus (HCV) as a cause of anti-phospholipid syndrome (APLS). Anti-cardiolipin antibodies (anti-CLAbs) in APLS are cofactor-dependent ('pathogenic' antibodies). We conducted a study in order to determine the prevalence of anti-CLAbs in HCV patients, and furthermore to address whether these autoantibodies are cofactor-dependent or not and whether they are associated with features of APLS. Patients with hepatitis B virus (HBV) were also evaluated in order to assess whether there are differences in the prevalence and the clinical significance of anti-CLAbs between these two major types of chronic viral hepatitis. MATERIALS AND METHODS: One hundred and seventy-four consecutive HCV patients, 50 HBV patients and 267 healthy were investigated for the presence of anti-CLAbs and antibodies against beta2-glycoprotein I (beta2-GPI), which is the most important cofactor of the 'pathogenic' anti-CLAbs in APLS. IgG anti-CLAbs were determined by an in-house quantitative ELISA and anti-beta2-GPIAbs using a commercial ELISA kit. RESULTS: 21.3% of the HCV and 14% of the HBV patients tested positive for IgG anti-CLAbs (P < 0.0001 compared with healthy controls). Neither age, sex, certain epidemiologic and laboratory parameters nor the clinical status and the histologic findings were associated with anti-CLAbs detection in both diseases. 2.3% of the HCV (P < 0.05 compared with healthy controls) and 2% of the HBV patients tested positive for anti-beta2-GPIAbs. Presence of anti-CLAbs was not associated with features of APLS. CONCLUSIONS: A significant proportion of the HCV and HBV patients had detectable IgG anti-CLAbs. However, the anti-CLAbs titres were relatively low, and in most cases seem to be cofactor-independent ('nonpathogenic'). The latter is further supported by the lack of their association with clinical features of APLS. Furthermore, anti-CLAbs appear to be detected irrespective of the demographic, laboratory, clinical and histologic status in both HCV and HBV. However, prospective studies of longer duration may be required in order to address whether anti-CLAbs in patients with chronic viral hepatitis are or are not of clinical importance. Eur J Clin Invest

OBJECTIVE: To study the prevalence of different causes of anaemia in patients with systemic lupus erythematosus (SLE) and their associations with immunological and clinical parameters and to evaluate the contribution of erythropoietin (Epo) and anti-erythropoietin (anti-Epo) autoantibodies to the development of SLE anaemia. METHODS: 132 SLE patients with anaemia (defined as haemoglobin of 12 g/dl or less for women and 13.5 g/dl or less for men) from among a total of 345 consecutive SLE patients were prospectively enrolled into the study. Standard haematological and immunological tests were performed and serum Epo and anti-Epo antibodies were assayed. RESULTS: The identified causes were anaemia of chronic disease (ACD) n=49 (37.1%), iron deficiency anaemia (IDA) n = 47 (35.6%), autoimmune haemolytic anaemia (AHA) n = 19 (14.4%) and other causes n = 17 (12.9%). There was significant heterogeneity in the severity of anaemia between the four groups (p

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti–DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

Northwestern Greece was identified in the 1960s for its high prevalence of endemic goiter and iodine deficiency. Although iodized salt has been commercially available since then, a recent epidemiological survey of 3916 schoolchildren found that low-grade goiter is still prevalent in endemic proportions (21%). The aim of this study was to further assess the cause of goiter and the severity of iodine deficiency in children from this endemic area of Greece. Of the 800 children with clinically detectable goiter, 97 children (60 girls and 37 boys, 8-15 years) were recruited for determination of urinary iodine excretion, as well as assessment of thyroid volume and function and detection of antithyroid antibodies. The median urinary iodine concentration was 8.4 microg/dL, indicative of a mild iodine deficiency. Thyroid function was normal in all but 11 children who had subclinical hypothyroidism. Sixteen children (16.5%), including all those with subclinical hypothyroidism, were positive for antithyroid antibodies. Their median urinary iodine concentration (20.6 microg/dL) was higher compared to children who were negative for antibodies (7.4 microg/dL; p

OBJECTIVE: Few studies have been carried out on the trace element status in patients with ulcerative colitis (UC). Many trace elements are critical for the normal development and function of the immune system. This study was conducted in order to assess the serum levels of zinc and copper and the possible interrelation(s) between them and various immunological markers in the circulation of well nourished patients with UC. DESIGN/METHODS: The serum levels of zinc, copper, soluble interleukin-2 receptors (sIL-2Rs), interleukin-1beta (IL-1beta), interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-alpha), non-organ specific autoantibodies (RF, ANA, ANCA, anti-dsDNA and anticardiolipin), C3C and C4 components of the complement system and ceruloplasmin were determined in 75 well nourished patients with UC (32 patients with active and 43 with inactive disease). Thirty-three healthy individuals were also investigated. RESULTS: The mean concentrations (microg/dl) of zinc and copper were significantly higher (P < 0.0005 and P = 0.0001, respectively) either in active (202.3 +/- 115.2 and 141.7 +/- 31.4, respectively) or in inactive disease (204.5 +/- 170.3 and 137.4 +/- 24.5, respectively) compared with healthy controls (93.6 +/- 49.8 and 85 +/- 41.2, respectively). The levels of copper were positively correlated with the C3C (r = 0.41, P < 0.0005), C4 (r = 0.38, P < 0.001) and ceruloplasmin (r = 0.44, P < 0.0005), whereas zinc was correlated with C3C (r = 0.32, P = 0.0005) and ANA (P = 0.01). Autoantibodies of at least one specificity (AUBS) were found in 77.3% of the patients. The mean levels (U/ml) of sIL-2Rs were significantly higher (P = 0.0001) in active disease (604.3 +/- 213.0) than in inactive UC (411.5 +/- 165.1) and in patients with ANA (P < 0.05), ANCA (P = 0.01) or AUBS (P < 0.05). The sIL-2Rs were correlated with the C4 (r = 0.40, P < 0.005) and the ESR (r = 0.43, P = 0.0001). CONCLUSION: These findings indicate that even in well nourished patients with UC, high serum levels of copper and zinc are present. The latter alterations of zinc and copper are correlated with haematological parameters of relapse of the disease or with acute phase proteins suggesting a relationship with the inflammatory process of UC. Further studies on the colonic tissue will address the role of zinc and copper in the inflammatory and immune reactions observed in this disease process. Eur J Gastroenterol Hepatol

The expression of a transgenic encoding the I-E alpha-chain, Ea(d), is highly effective in the protection from systemic lupus erythematosus (SLE) in BXSB and (MRL x BXSB)F1 male mice, in which a mutant gene, Yaa (Y-linked autoimmune acceleration), plays a critical role. To gain further insight into the protective role of the Ea(d) transgene, we compared the effect of the transgene in two additional lupus-prone (NZB x BXSB)F1 and (NZW x BXSB)F1 hybrid mice, in which both F1 female mice develop typical SLE in the absence of the Yaa gene and their F1 males bearing the Yaa gene develop a more accelerated form of SLE. Comparative analysis of the clinical development of SLE in these F1 hybrid mice showed that Ea(d) transgene expression was much more effective in the protection from SLE occurring in the F1 females than in their male counterparts. Our results indicate that the Ea(d) transgene is capable of preventing SLE by inhibiting autoimmune responses, independently of the Yaa gene-accelerating effect, and that its protective capacity is strongly influenced by the genetic susceptibility to SLE in individual strains of lupus-prone mice. In addition, this autoimmune inhibitory effect was shown to be selective for IgG, but not IgM, anti-DNA autoantibody production, and is more specific for anti-gp70 autoantibody than for anti-DNA autoantibody. These results favour the hypothesis that the transgene expression may lead to the modulation of self-peptide presentation, thereby preventing excessive T-cell-dependent activation of autoreactive B cells.

To determine the diagnostic accuracy of a new point-of-care assay detecting anti-deamidated gliadin peptides in celiac disease (CD) patients.One-hundred-and-twelve patients (age range: 1.8-79.2 years old) with clinical symptoms suggestive of CD and/or first-degree relatives (FDR) of CD patients (n = 66), and confirmed CD on a gluten-free diet (GFD) (n = 46), were prospectively enrolled in the study at Gastroenterology outpatient clinics for adult patients and from the Gastroenterology Consultation Ward at the Pediatric Department of the University Hospital of Geneva. Written informed consent was obtained from all subjects enrolled. The study received approval from the local ethics committee. The original CD diagnosis had been based on serum-positive IgA anti-tissue transglutaminase enzyme-linked immunosorbent assay (ELISA) (QuantaLite™, Inova Diagnostics, San Diego, CA, United States) and on biopsy results. Serum samples from all study participants were tested by the new CD lateral flow immunochromatographic assay (CD-LFIA) device, Simtomax® Blood Drop (Augurix SA, BioArk, Monthey, Switzerland) to detect immunoglobulin (Ig)A and IgG antibodies against deamidated gliadin peptides. The diagnostic performance was evaluated using receiver operating characteristic curves with 95%CIs. A cut-off of 2 on the Rann colorimetric scale was used to calculate the device's sensitivity and specificity.CD-LFIA was highly accurate in detecting untreated celiac patients. In the group of patients with CD symptoms and/or FDR, eight new cases of CD were detected by ELISA and biopsy. All of these new cases were also correctly identified by CD-LFIA. The test yielded four false positive and four false negative results. The false positive results were all within the groups with clinical symptoms suggestive of CD and/or FDR, whereas the false negative results were all within the GFD group. The test yeld a sensitivity of 78.9% (95%CI: 54.4-93.9) and specificity of 95.7% (95%CI: 89.4-98.8), and the area under the curve reached 0.893 (95%CI: 0.798-0.988). The Kappa coefficient, calculated according to the values obtained by two readers from the same device, was of 0.96 (SE: 0.06). When the GFD patients were excluded from the analysis, the area under the curve reached 0.989 (95%CI: 0.971-1.000) and the Kappa coefficient, calculated according to the values obtained by two readers from the same device, became 0.96 (SE: 0.07). Furthermore, using the Rann scale cut-off of 2 without the GFD patients, sensitivity was 100% and specificity was 93.1% (95%CI: 83.3-98.1).The new CD-LFIA rapid screening test shows good diagnostic accuracy, sensitivity and specificity, and may rule out CD in patients with CD-related symptoms.

SLE pathogenesis is complex, but it is now widely accepted that autoantibodies play a key role in the process by forming excessive immune complexes; their deposits within tissues leading to inflammation and functional damages. A proliferation inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) superfamily mediating antibody-producing plasma cell (PC)-survival that may be involved in the duration of pathogenic autoantibodies in lupus. We found significant increases of APRIL at the mRNA and protein levels in bone marrow but not spleen cells from NZB/W lupus mice, as compared to control mice. Selective antibody-mediated APRIL blockade delays disease development in this model by preventing proteinuria, kidney lesions, and mortality. Notably, this was achieved by decreasing anti-DNA and anti-chromatin autoantibody levels, without any perturbation of B- and T- cell homeostasis. Thus, anti-APRIL treatment may constitute an alternative therapy in SLE highly specific to PCs compared to other B-cell targeting therapies tested in this disease, and likely to be associated with less adverse effects than any anti-inflammatory and immunosuppressant agents previously used.

The purpose of this study was the descriptive analysis of patients with systemic lupus erythematosus (SLE) with a particular focus on initial clinical features, evolution and outcome of disease, prevalence of clinical and serological manifestations and identification of clinicoserological associations indicative of renal and CNS involvement. The methodology applied was the following: retrospective analysis of the clinical charts of 292 unselected patients (246 female (84.2%) and 46 male (15.7%)) with SLE examined between 1982 and 1992. Multivariate analysis and hierarchical log linear models were used to examine for clinicoserological associations. Descriptive analysis was based on the prevalence of main clinicoserological features and disease outcome. The outcome was examined on the basis of the number of flares, the presence of chronic renal failure, the presence of central nervous system (CNS) involvement with subsequent disability and deaths. Flares were considered the severe alterations in disease status, requiring additional therapy to be controlled. The disease begins most frequently in the second and third decade of life with cutaneous and joint manifestations, while renal and CNS involvement developed later. The prevalence of serious renal, pulmonary and CNS involvement as well as the prevalence of RF, anti-Sm and anti-nRNP antibodies remain low. Multivariate analysis revealed the associations of renal involvement with leukopenia and serositis, of anti-Sm with leukopenia, of secondary Sjogren's syndrome with RF and of thromboembolic events with anticardiolipin antibodies. Patients with childhood onset SLE have a higher tendency for developing renal involvement than adult onset SLE patients. In addition, anti-Ro(SSA) antibodies were associated with anti-La(SSB) and RF, while anti-Sm antibodies were associated with anti-nRNP and RF. Flares occurred with a frequency of 0.07 per patient per year. Only 63.6% of flares were accompanied by positive anti-dsDNA reactivities. Reported deaths were 0.0047 per patient per year. Hierarchical log linear models indicated that the main variables of the disease were sufficient to describe our disease model and that the order of the interaction between the variables was insignificant. We conclude that the prevalence of various clinical features associated with SLE is similar, although the prevalence of CNS and pulmonary involvement as well as anti-Sm and anti-nRNP antibodies are less prominent in Greek SLE patients than that reported in the literature. The various clinicoserological associations detected do not appear to be of major significance as they are not powerful enough to subgroup the disease. Lupus

Eight cases of D-penicillamine (DP) induced myasthenia gravis (MG) are presented. Seven patients were being treated for rheumatoid arthritis (RA) and one for scleroderma. The mean duration of DP treatment until the myasthenic symptoms developed ranged from 2-8 months. The DP dose reached 500 mg daily. It was found that the clinical and immunological findings were almost similar to those of idiopathic MG, but were less severe. All patients had increased titers of acetylcholine receptor antibodies in their sera. Discontinuation of D-penicillamine resulted in the complete resolution of myasthenic symptoms after 2-6 months. One patient required ventilation, immunosuppressive therapy and plasma exchange. No association was found between DP related MG and the various autoantibodies tested. Immunogenetic analysis showed that three patients had HLA-DR1, two HLA-DR3, one HLA-DR4 and one HLA-DR5. In conclusion, the clinical presentation of DP-induced MG seems similar to idiopathic MG. DP-related MG is relatively benign, although it sometimes can cause life-threatening muscle weakness requiring aggressive therapy. The relatively small number of patients included in this study, however, does not permit any firm conclusions regarding the HLA associations of DP-related MG. Clin Exp Rheumatol

To assess the degree of immune system activation associated with addiction or hepatotropic viruses infection, we examined 60 HIV-negative heroin addicts for the presence of hepatitis B virus (HBV) infection markers, hepatitis C virus antibodies (anti-HCV), various auto-antibodies, and serum levels of soluble interleukin-2 receptors (sIL-2R). In addition, 28 anti-HCV positive patients comprising the disease control group, were also examined. Our results demonstrated a high prevalence of anti-HCV antibodies (61.7% and 90% with 1st and 2nd generation ELISA, respectively). Eighty-seven percent (87%) of the addicts positive for anti-HCV by the latter and 92.8% of the disease control patients, were also positive with 2nd generation recombinant immunoblot assay (RIBA-II). In 88.9% of anti-HCV positive addicts, antibody to C22-3 was the predominant (anti-C33c in 81.5%). Antibodies to C33c and C22-3 polypeptides were also more frequent in disease control group (92.8% and 85.7%, respectively). Anti-HCV antibodies were associated with increased transaminases (ALT or AST, P < 0.05), as well as with longer duration of addiction (P < 0.005). HBV infection markers (HBsAg, anti-HBc only and anti-HBs) were also present in the addicts (5%, 28.3% and 26.7%, respectively). Rheumatoid factors (RF) were detected in 36.7%, antinuclear antibodies (ANA) in 11.7%, antibodies (IgG and/or IgM) against cardiolipin (anti-CL) and double stranded DNA (anti-ds DNA) in 20% and 50%, respectively. RF, ANA, anti-CL and anti-dsDNA antibodies were also detected in the disease control group (32.1%, 89.3%, 28.5% and 28.5% respectively).(ABSTRACT TRUNCATED AT 250 WORDS) Eur J Clin Invest

We investigated the clinical features and outcome of 60 patients with antineutrophil cytoplasmic autoantibodies with cytoplasmic staining (C-ANCA)- and with (peri)nuclear staining (P-ANCA)-associated glomerulonephritis. Virtually all patients with C-ANCA had antibodies against proteinase 3, which corresponded with a clinical and/or histological diagnosis of Wegener's granulomatosis (WG). P-ANCA were associated with antibodies against myeloperoxidase. Although more often associated with renal-limited disease, a significant number of patients with P-ANCA had also symptoms of organs known to be preferentially affected with WG. The majority of patients presented with rapidly progressive glomerulonephritis which responded favorably to immunosuppressive therapy, albeit at the expense of a considerable number of fatal infections. Furthermore, a more protracted form of glomerulonephritis was recognized. A kidney biopsy scoring system appeared to be of value in predicting which patients would benefit most from treatment. C-ANCA and P-ANCA appear to identify a subset of patients with vasculitis that share common clinical features and a favorable response to immunosuppressive therapy.