Antibody-negative Patients Research Articles

Brief Report: Attenuated Effectiveness of Tumor Necrosis Factor Inhibitors for Anti-Human T Lymphotropic Virus Type I Antibody-Positive Rheumatoid Arthritis.

To evaluate the effectiveness of tumor necrosis factor (TNF) inhibitors for the treatment of human T lymphotropic virus type I (HTLV-I)-positive patients with rheumatoid arthritis (RA) in an area endemic for HTLV-I infection. We conducted an observational study of 585 RA patients in whom TNF inhibitors were newly introduced as a first biologic disease-modifying antirheumatic drug in an area in southwestern Japan that is endemic for HTLV-I infection. Fifty patients (8.5%) were anti-HTLV-I antibody-positive. The ages of the patients in this group were significantly higher at entry compared with the ages of patients who were anti-HTLV-I antibody-negative (n = 535). The median Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was 5.21. Among the total group of patients, 82% were anti-citrullinated protein antibody (ACPA)-positive. The persistence rate of TNF inhibitors at 24 weeks was 89%. The median DAS28-ESR was significantly decreased at 24 weeks in each group. The European League Against Rheumatism (EULAR) response rate was significantly better in the anti-HTLV-I antibody-negative patients (P = 0.0277). Multiple regression analysis demonstrated that anti-HTLV-I antibody status was significantly associated with the EULAR response rate and change in the DAS28-ESR and was prominent especially in the ACPA-negative subjects. No patients developed adult T cell leukemia/lymphoma (ATL) or HTLV-I-associated myelopathy (HAM) during the 24-week treatment period. The efficacy of TNF inhibitors may be attenuated in anti-HTLV-I antibody-positive patients with RA. ATL and HAM did not develop when TNF inhibitors were used for 24 weeks, but the long-term risk is not known.

Low or Undetectable Basal Thyroglobulin Levels Obviate the Need for Neck Ultrasound in Differentiated Thyroid Cancer Patients After Total Thyroidectomy and 131I Ablation.

Neck ultrasound (NUS) is currently seen as a main component of follow-up of differentiated thyroid cancer (DTC) and is usually performed regardless of non-stimulated thyroglobulin (Tg) levels. The aim of this study was to determine whether there is a clinical benefit from such a routine NUS in DTC patients. A retrospective database study was conducted of 3176 cervical ultrasound exams performed in 773 patients between June 15, 1996, and July 1, 2012. The accuracy of ultrasound results was assessed based on the results of further diagnostic and/or therapeutic procedures within six months of a particular ultrasound. A total of 2199 NUS exams were classified as true negative, 216 as true positive, 692 as false positive in 339 (43.9%) individual patients, 170 of whom were low risk, and 69 as false negative. Thus, overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy [confidence interval] were 75.8% [70.1-81.5%], 76.1% [74.3-77.8%], 23.8% [18.1-29.5%], 97.0 [96.2-97.7%], and 76.0% [74.3-77.7%], respectively. No significant differences were found between low- and high-risk patients. There were no significant differences between patients with an undetectable and a low detectable (<1 μg/L) Tg level. However, these two groups both showed significantly lower positive predictive value and higher negative predictive value than patients with a Tg ≥1 μg/L. From January 2007 onwards, true-positive and false-negative neck ultrasounds were no longer observed in patients with Tg <1 μg/L. After total thyroidectomy and 131I ablation, neck ultrasound should be reserved only for anti-Tg antibody negative patients with a Tg level of ≥1 μg/L.

Expression of leukocyte immunoglobulin-like receptor A3 in CD14+ monocytes of patients with rheumatoid arthritis

To investigate the expression of leukocyte immunoglobulin-like receptor A3 (LILRA3) in CD14+ monocytes of patients with rheumatoid arthritis (RA). Fifty three RA patients admitted in the Second Affiliated Hospital of Zhejiang University School of Medicine from February 2017 to August 2017, and 21 healthy subjects were enrolled in the study. The expression of LILRA3 in CD14+ monocyte subset was determined by flow cytometry, and its correlations with clinical features, laboratory examination results, antibodies and disease activity were analyzed. LILRA3 percentage in the CD14+ monocyte subset of RA patients was higher than that in the healthy controls (P<0.01). The percentage of LILRA3 was positively correlated with number of tenderness joints, number of swollen joints and erythrocyte sedimentation rate (r=0.280, 0.371, 0.341, P <0.05 or <0.01), but was not correlated with the age, course of disease, Sharp score, C reactive protein, blood routine index and immunoglobulin (all P>0.05). In addition, the percentages of LILRA3 in the monocytes of rheumatoid factor (RF)-positive or anti-cyclic citrullinated peptide (CCP) antibody-positive patients were significantly higher than those of the RF-or anti-CCP antibody-negative patients (all P < 0.05); and the percentage of LILRA3 in patients with DAS28>5.1 was higher than that in patients with DAS28 ≤ 5.1 (P<0.05). The expression of LILRA3 is up-regulated in CD14+ monocyte subset isolated from RA patients, and it is correlated with disease activity.

Diagnosis and treatment of anti-myelin oligodendrocyte glycoprotein antibody positive optic neuritis.

Anti-myelin-oligodendrocyte glycoprotein (MOG) antibody positive optic neuritis has been established as a new subset of optic neuropathy. Anti-MOG antibodies are usually measured by cell-based assay. Patients with anti-MOG antibody positive optic neuritis respond well to steroid therapy, and, while visual acuity outcomes are favorable, significant visual field defects remain. Furthermore, patients who are anti-MOG antibody positive have higher rates of recurrence compared to antibody negative patients. Based on these findings, anti-MOG antibody positive patients with optic neuritis have the characteristics of good visual outcomes, residual visual field defects, and high risk of recurrence. Tests for anti-MOG antibody are useful for the diagnosis and treatment of optic neuritis.

Esophageal high-resolution impedance manometry alterations in asymptomatic patients with systemic sclerosis: prevalence, associations with disease features, and prognostic value.

This study aims to investigate pre-clinical esophageal involvement in systemic sclerosis (SSc) by high-resolution impedance manometry (HRiM), its associations with disease features including lung involvement, and its predictivity of esophageal symptoms overtime. Charts of 45 asymptomatic (no heartburn/regurgitation/dysphagia) SSc patients (96% females; mean age 46years) with at least one follow-up (FU) visit and complete clinical, serological, functional, and radiological assessment, including high-resolution computed tomography (HRCT) of the chest and lung function tests, that had undergone esophageal HRiM were retrospectively evaluated. Esophagogastric junction-contractile integral (EGJ-CI) and esophageal body motility, as evaluated by mean distal contractile integral (DCI), were assessed. SSc patients had a normal esophageal motility in 7/45 cases, a defective EGJ-CI in 28, an ineffective esophageal motility (IEM) in 17, and aperistalsis in 12. Defective EGJ-CI was associated with IEM/aperistalsis in 20 cases, while 9 patients had isolated IEM. Defective EGJ-CI and/or IEM/aperistalsis were associated with a diffusing lung capacity for CO < 80% of predicted value (all p < 0.05), while defective EGJ-CI was also associated with interstitial lung disease on HRCT (p = 0.03). Prevalence of any HRiM abnormality was higher in anti-centromere antibody negative patients (all p < 0.05). IEM/aperistalsis independently increased the risk of esophageal symptoms by 2.3-fold (95% CI 1.1-5.7) and was associated with their higher cumulative incidence with respect to patients with other HRiM patterns at FU (χ2 = 4.63; p = 0.03). SSc patients asymptomatic for esophageal involvement can have HRiM abnormalities in up to 84% of cases. A baseline-impaired motility is a risk factor for symptomatic esophageal disease.

Clinical significance of humoral immunity against XAGE1 cancer-testis antigen in lung adenocarcinoma.

162 Background: Cancer-testis antigens (CTAs) are expressed predominantly in the testis and various types of cancer. Some of CTAs are highly immunogenic and attractive targets for cancer immunotherapy. We identified XAGE1 as a dominant CTA in lung adenocarcinoma (LAD). In this study, we examined immune responses to XAGE1 and the clinical significance in LAD patients. Methods: Expression of XAGE1 and immune checkpoint molecules in LAD tissues was determined by immunohistochemistry. The XAGE1 antibody and T cell immune responses were analyzed in blood samples. Then, overall survival (OS) of the XAGE1 antigen-positive and -negative, and XAGE1 antibody-positive and -negative patients was analyzed. Results: The XAGE1 antigen was expressed in approximately 40% of LAD, and the expression reflected shortened OS of pStage I-IIIA LAD in two japanese cohorts. In addition, expression profiles of XAGE1 and immune checkpoint molecules of PD-L1 and galectin-9 on tumor cells efficiently predicted OS of pStage I-IIIA LAD patients. The XAGE1 antibody response was observed in 6% (9/155) of our pStage I-IIIA, and 20% (34/167) of cStage IIIB-IV LAD, respectively, showing a higher antibody response rate in more advanced stages. In the antibody-positive patients, CD4 and CD8 T cell responses were frequently elicited, and phenotypic and functional analyses of T cells indicated immune activation. Furthermore, the OS of antibody-positive patients significantly prolonged as compared with that of antibody-negative patients with either XAGE1 antigen-positive EGFRwt (31.5 vs 15.6 months, P = 0.05) or EGFRmt (34.7 vs 11.1 months, P = 0.001) LAD. Multivariate analysis showed that the XAGE1 antigen expression was a worse predictor in EGFRmt LAD (HR: 5.23). On the other hand, the presence of the XAGE1 antibody was a strong predictor for prolonged OS in XAGE1 antigen positive LAD (HR: 0.18) and in either EGFRwt or EGFRmt LAD. Conclusions: The XAGE1 antigen induced strong immune responses in LAD patients with more advanced stages, and the production of XAGE1 antibody in these patients showed good prognosis. Our results indicate that the XAGE1 immunity is probably a good prognostic biomarker in LAD and a promising target for immunotherapy of LAD.

Pitfalls in clinical diagnosis of anti-NMDA receptor encephalitis.

To report pitfalls in the clinical diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. We retrospectively reviewed the clinical information of 221 patients with clinically suspected autoimmune neurological disorders who underwent testing for autoantibodies against neuronal cell-surface antigens between January 1, 2007 and September 10, 2017. Forty-one patients met the diagnostic criteria for probable anti-NMDAR encephalitis (probable criteria), but one was excluded because neither serum nor CSF was examined at the active stage. Thus, in 220 patients, sensitivity and specificity of the probable criteria were assessed. NMDAR-antibodies were detected in 34 of 40 patients (85%) with the probable criteria; however, 2 of the 6 antibody-negative patients had ovarian teratoma. The median age at onset was higher in antibody-negative patients than those with antibodies (49 vs. 27years, p=0.015). The age at onset was associated with the probability of antibody detection (p=0.014); the probability was less than 50% in patients aged 50years or older. NMDAR-antibodies were also detected in 5 of 180 patients who did not fulfill the probable criteria; these patients presented with isolated epileptic syndrome (n=2), atypical demyelinating syndrome (n=2; one with aquaporin 4 antibodies), and autoimmune post-herpes simplex encephalitis (post-HSE) (n=1). Sensitivity and specificity of the probable criteria was 87.2 and 96.7%, respectively. The probable criteria are valid, but the diversity of clinical phenotype should be taken into account in diagnosing anti-NMDAR encephalitis particularly in patients aged 50years or older, or with isolated epileptic syndrome, atypical demyelinating syndrome, or post-HSE.

Percutaneous laser ablation of benign thyroid nodules: a one year follow-up study.

ABSTRACTObjective To evaluate safety and effectiveness of nodule volume reduction and thyroid function after percutaneous laser ablation treatment in patients with benign nonfunctioning thyroid nodules.Methods Prospective single-center study, from January 2011 to October 2012, which evaluated 30 euthyroid and thyroid antibodies negative patients with benign solitary or dominant nodule with indication of treatment due to compressive symptoms and aesthetic disturbances. The clinical and laboratory (thyroid ultrasound, TSH, FT4, TG, TG-Ab, TPO-Ab and TRAb levels) evaluations were performed before the procedure, and periodically 1 week, 3 months and 6 months after. The ablation technique was performed under local anesthesia and sedation. In each treatment, one to three 21G spinal needle were inserted into the thyroid nodule. The laser fiber was positioned through the needle, which was then withdrawn 10mm to leave the tip in direct contact with the nodule tissue. Patients were treated with a ND: Yag-laser output power of 4W and 1,500 to 2,000J per fiber per treatment. The entire procedure was performed under US guidance.Results Thirty patients, with a total of 31 nodules submitted to laser ablation were evaluated. The median volumetric reduction of the nodule was approximately 60% after 12 months. No statistical significance was observed on thyroid function and antibodies levels. There was a peak on the level of thyroglobulin after the procedure due to tissue destruction (p<0.0001). No adverse effects were observed.Conclusion Percutaneous laser ablation is a promising outpatient minimally invasive treatment of benign thyroid nodule.

The incidence and clinical relevance of anti-HLA and/or MICA antibodies in patients with long-term survival renal allo-grafts

The purpose of this study was to analyze the incidence and clinical relevance of anti-HLA and/or MICA antibodies in renal allo-grafts transplant recipients with long-term renal survival (> 5 years). This retrospective study collected post-transplant serum samples from a total of 110 patients which were used to detect the incidence of anti-HLA and/or MICA antibodies as well as anti-HLA donor specific antibodies. Among these 110 patients, 72 patients had antibodies against HLA and/or MICA at the time of test, 61 had only anti-HLA antibodies, 31 had anti-MICA antibodies, and 38 were antibody negative. There was no difference in the number of patients developing antibodies against non-donor specific antibodies, donor specific antibodies, Class I donor specific antibodies, Class II donor specific antibodies or MICA antibodies between normal function group (serum creatinine level < 2.0 mg/dL) and dysfunction group (serum creatinine level > 2.0 mg/dL). For the serum creatinine level, estimated glomerular filtration rate and blood urea nitrogen level, patients with different antibodies were not statistically different to antibody-negative patients. Cox regression analysis showed that the type of transplantation and HLA mismatch number were significant negative risk factors for the development of anti-HLA (P < 0.05). Our results suggested that the anti-HLA antibody status has little impact on the renal graft function in the long-term survival allo-graft renal recipients.

Detection of circulating IgG autoantibody to FcεRIα in sera from chronic spontaneous urticaria patients.

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by itchy wheals of at least 6 weeks in duration, wherein the autoimmune mechanism is involved to activate IgE receptors (FcεRIα) on mast cells. We aimed to assess levels of IgG autoantibody against FcεRIα in sera from CSU patients using dot-blot immunoassay. We performed a hospital-based cross-sectional study of 125 CSU patients (64 ASST-positive, 61 ASST-negative) and 64 age-and sex-matched healthy controls. The cut-off value of IgG FcεRIα autoantibody was determined as the mean intensity plus two standard deviations of values in controls. Positivity for IgG autoantibody to FcεRIα was analyzed according to clinical parameters of disease duration, urticaria activity score (UAS), ASST, response to antihistamine treatment, complement levels, and the presence of other autoantibodies. Nonparametric tests were applied for statistical analyses. IgG positivity to FcεRIα was noted in 24.8% of CSU patients and was significantly more frequent in ASST-positive patients than in ASST-negative patients (32.8% vs 16.4%, P=0.040). Only 3.1% of healthy controls had this autoantibody. Complement 3 levels were significantly lower in anti-FcεRIα antibody-positive patients than antibody-negative patients (109.8±19.9 vs 123.1±30.9, P=0.035). No significant associations were found between IgG positivity to FcεRIα and UAS, serum total IgE levels, atopic status, clinical responses to antihistamines, or the presence of anti-thyroid and anti-nuclear antibodies. These findings suggest that circulating IgG autoantibody to FcεRIα in a subset of patients may be involved in the autoimmune mechanism of CSU. Further studies are needed to clarify its clinical significance.

Less Limb Muscle Involvement in Myositis Patients with Anti-Mitochondrial Antibodies

Recent studies have revealed the clinical, histological, and pathophysiological characteristics in a group of inflammatory myopathies with selected autoantibodies. We retrospectively compared the clinical manifestations and histological features between 8 anti-mitochondrial (anti-M2) antibody-positive and 33 antibody-negative patients. Patients with anti-M2 antibodies have been previously reported to have delayed diagnostic confirmation and frequent cardiopulmonary complications in comparison to those without the antibodies. In our study, clinical characteristics in patients with the antibodies were as follows: lesser degree of limb muscle weakness and atrophy as well as lymphocytic infiltration in muscle biopsy specimens, and frequent paravertebral muscle atrophy. Anti-M2 antibody appeared to be a biomarker related to not only cardiopulmonary complications, but also characteristic ­distributions of affected muscles.

Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies

Previous estimates of risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-John Cunningham virus (JCV) antibodies in serum, previous immunosuppressant use, and treatment duration, which were estimated using population-based assumptions. We aimed to calculate PML risk estimates from patient-level risk-factor data and to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index). Data on natalizumab-treated patients were pooled from four large, observational, open-label studies: STRATIFY-2, STRATA, TOP, and TYGRIS. Data were analysed with and without imputation for missing values of anti-JCV antibody status and previous immunosuppressant use. For anti-JCV antibody-positive patients in this pooled cohort, cumulative PML risk with or without previous immunosuppressant use was estimated using Kaplan-Meier analysis. Annual PML risks (per 12 natalizumab infusions) for patients without PML in the preceding year were estimated using conditional probability based on the life table method. For anti-JCV antibody-positive patients without previous immunosuppressant use, risk estimates were further stratified using a probability distribution for anti-JCV antibody index values, separately for patients with or without PML. Anti-JCV antibody index cutoffs were selected via sensitivity and specificity assessments for identifying PML cases in an index cohort. 156 (<1%) of 37 249 patients in the pooled cohort had PML. We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immunosuppresant use (544 patients) using a multiple imputation method. For anti-JCV antibody-negative patients (n=13 996), estimated PML risk was less than 0·07 per 1000 patients (95% CI 0·00-0·40). In anti-JCV antibody-positive patients (n=21 696), estimated cumulative PML probability over 6 years (72 infusions of natalizumab) was 2·7% (95% CI 1·8-4·0) in patients with previous immunosuppressant use and 1·7% (1·4-2·1) in those without. In patients without previous immunosuppressant use (n=18 616), estimated annual PML risks per 1000 patients, conditional on having no PML before that year, ranged from 0·01 (0·00-0·03) in year 1 (1-12 infusions) to 0·6 (0·0-1·5) in year 6 (61-72 infusions) for people with an index of 0·9 or less; from 0·1 (0·0-0·2) in year 1 to 3·0 (0·2-5·8) in year 6 for those with an index of more than 0·9 up to and including 1·5; and from 0·2 (0·0-0·5) in year 1 to 10·0 (5·6-14·4) in year 6 for those with an index of more than 1·5. Our risk estimates calculated from patient-level clinical data allow individualised annual prediction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly benefit-risk re-evaluation in clinical practice. Further, our estimates are generally consistent with previously calculated estimates. Incorporating anti-JCV antibody index allows further risk stratification for anti-JCV antibody-positive patients who have not previously taken immunosuppressants. Biogen.

High prevalence of neuronal surface autoantibodies associated with cognitive deficits in cancer patients.

The recent discovery of neuronal cell-surface antibodies profoundly expanded the clinical spectrum of paraneoplastic neurological syndromes. Many of these syndromes are associated with impaired cognitive function, a clinical symptom that is of increasing concern in cancer patients. However, the frequency of these antibodies in cancer patients and their relation to clinical syndromes is currently unknown. Here, we investigated the prevalence of neuronal cell-surface antibodies and associated paraneoplastic neurological syndromes in 323 patients with different cancer types and in 105 controls. Cerebrospinal fluid and serum samples were analysed for a large panel of anti-neuronal antibodies and all patients were screened for cognitive deficits. Blood-brain barrier integrity was assessed using the age-normalized albumin cerebrospinal fluid/serum ratio. Anti-neuronal autoantibodies were observed in 24.5% of cancer patients (in contrast to 3.1% in neurological control patients without cancer and 2.5% in healthy controls) and were almost exclusively detected in serum. The majority of antibodies were directed against cell-surface antigens (75.9%), most frequently IgA/IgM isotypes targeting the N-methyl-D-aspartate (NMDA) receptor. Cognitive deficits and cerebellar syndromes were significantly more prevalent in antibody-positive in comparison with antibody-negative patients (21 vs. 7%, p=2.7×10-4; 11 vs. 2%, p=3.0×10-3). Antibody-positive patients with cognitive deficits had a significantly increased albumin cerebrospinal fluid/serum ratio in comparison with antibody-positive patients with other neurological deficits, indicating blood-brain barrier dysfunction (49.1×10-3 vs. 12.0×10-3; p=0.036). Our results show that anti-neuronal antibodies have a high prevalence in a wide range of different tumour types and are associated with distinct neurological deficits. Specifically, the results suggest a so far undefined cognitive paraneoplastic syndrome in patients with antibodies targeting neuronal surface antigens and concurrent blood-brain barrier dysfunction. Anti-neuronal antibodies might thus serve as a biomarker for potentially treatment-responsive cognitive impairments in cancer patients.

Anti-neutrophil cytoplasmic antibodies in new-onset systemic lupus erythematosus.

BackgroundThe clinical significance of anti-neutrophil cytoplasmic antibodies in patients with new-onset systemic lupus erythematosus, especially in systemic disease accompanied by interstitial lung disease remains to be elucidated.ObjectivesThis study was designed to investigate the role of anti-neutrophil cytoplasmic antibodies in new-onset systemic lupus erythematosus patients.MethodsA hundred and seven patients with new-onset SLE were enrolled. Presence of anti-neutrophil cytoplasmic antibodies in the sera was assessed by indirect immunofluorescence as well as enzyme linked immunosorbent assay against proteinase-3 and myeloperoxidase. Clinical features and laboratory parameters of patients were also recorded. All patients were subjected to chest X-ray, chest high-resolution computed tomography and pulmonary function test.ResultsForty-five systemic lupus erythematosus patients (45/107, 42%) were seropositive for anti-neutrophil cytoplasmic antibodies. Compared with anti-neutrophil cytoplasmic antibodies-negative patients, the anti-neutrophil cytoplasmic antibodies-positive patients had significantly higher incidence of renal involvement, anemia, and Raynaud's phenomenon as well as decreased serum level of complement 3/complement 4 and elevated erythrocyte sedimentation rate. In addition, there was a positive correlation between serum anti-neutrophil cytoplasmic antibodies level and disease activity of systemic lupus erythematosus. Furthermore, prevalence of interstitial lung disease in the anti-neutrophil cytoplasmic antibodies -positive patients (25/45, 55.6%) was obviously higher than that in the anti-neutrophil cytoplasmic antibodies-negative patients (15/62, 24.2%).Study limitationsThe sample size was limited and the criteria for screening new-onset systemic lupus erythematosus patients might produce bias.ConclusionsThe level of anti-neutrophil cytoplasmic antibodies in new-onset systemic lupus erythematosus patients correlates positively with the disease activity and the prevalence of interstitial lung disease.

Significance of antibodies to ribosomal P proteins in lupus nephritis patients and their relation to disease activity: clinical and laboratory study

BackgroundLupus nephritis (LN) is a prominent feature in systemic lupus erythematosus (SLE), present in 15–30% of patients with lupus at the time of the initial diagnosis and in 30–50% during the disease progression.ObjectivesThe aim of this study was to determine the significance of anti-ribosomal P protein (anti-P) antibodies and LN and their relation to disease activity and other SLE manifestations.Patients and methodsFifty active LN patients were subjected to full clinical examination (assessment of SLE disease activity using the systemic lupus erythematosus disease activity index and assessment of SLE disease severity using Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), routine laboratory investigations, anti-dsDNA antibodies, and anti-P antibodies.ResultsComparison between the data of LN in both groups (anti-P positive/anti-dsDNA negative and anti-P negative) shows that there was a statistically significant difference in age (P=0.042), hypertension (P=0.00), and psychiatric manifestations (P=0.004). On comparison of both groups as regards vasculitis, there was a borderline statistical significance (P=0.050). Comparison of both groups as regards creatinine level or biopsy class V showed a statistically significant difference with a higher percentage in the anti-P positive/anti-dsDNA negative group (P=0.024 and 0.040, respectively).ConclusionAnti-P antibody-positive patients have younger ages, lower creatinine level, lower incidence of hypertension, usually class V in renal biopsy, but more susceptible to have psychiatric manifestations compared with anti-P antibody negative patients.

Reduction of annexin A5 anticoagulant ratio identifies antiphospholipid antibody‐positive patients with adverse clinical outcomes

Essentials Annexin A5 resistance is a mechanism for antiphospholipid (aPL) syndrome. 750 patients with history of thrombosis, pregnancy complications and controls were tested. Reduced annexin A5 anticoagulant ratios (A5R) correlate with aPL antibody multipositivity. Reduced A5R may identify patients with a propensity for thrombosis or pregnancy complications. Click to hear an ISTH Academy presentation on antiphospholipid antibody syndrome by Drs de Laat and Bertolaccini SUMMARY: Background Annexin A5 (A5) is a potent anticoagulant protein that shields anionic phospholipids from coagulation reactions. Previous studies showed that antibodies from patients with antiphospholipid (aPL) syndrome (APS) interfere with annexin A5 crystallization and anticoagulant activity. Objective The purpose of this study was to investigate whether reduced values in the annexin A5 anticoagulant ratio (A5R) assay (i.e. 'annexin A5 resistance') are associated with adverse clinical events in aPL antibody-positive patients. Patients/Methods In an initial discovery phase, a group of 679 patient samples from a 'real-world' tertiary care hospital population were tested for A5R. This was followed by a validation-phase cohort of 71 asymptomatic patients with aPL antibodies and no prior history of an adverse clinical event whose baseline samples were tested for A5R then subsequently observed for up to 4 years. Results In the discovery-phase group, we found a reduction of A5R in aPL antibody-positive patients with thrombosis and/or pregnancy complications compared with aPL antibody-negative patients and controls. In addition, reduced A5R values in both the discovery-phase group and validation-phase cohort correlated with the extent of multi-positivity for standard APS tests, which has also been shown to be associated with a risk of adverse clinical outcomes. Conclusion Reduced A5R values were associated with a multi-positivity profile in aPL antibody-positive patients within both groups and with the development of adverse clinical events.

An investigation of the relationship between recurrent spontaneous abortion and memory T follicular helper cells.

Immune tolerance with respect to a semi-allogeneic fetus plays a key role in the establishment of a pregnancy. Memory T follicular helper (Tfh) cells have a central role in the regulation of the adaptive immune response. Much of our knowledge of memory Tfh cells' function comes from immune-related diseases. However, the true physiological characteristics of memory Tfh cells and their mode of action in pregnancy remain unclear. Deciduas and blood were obtained from 25 recurrent spontaneous abortion (RSA) patients undergoing surgical abortion and 19 normal women in early pregnancy undergoing elective termination. RSA patients were grouped into antibody-positive patients and antibody-negative patients, respectively. The memory Tfh cells with the CD4+ CXCR5+ PD1+ CCR7- and CD4+ CXCR5+ PD-1+ ICOS+ phenotypes were assessed by flow cytometry. The B cells were evaluated by flow cytometry. A correlation analysis of the subsets of memory Tfh cells and B cells in antibody-positive RSA patients was made by the Pearson test. Memory Tfh cells with the CD4+ CXCR5+ PD1+ CCR7- and CD4+ CXCR5+ PD-1+ ICOS+ phenotypes showed a significant increase in RSA patients compared to women with a normal pregnancy who had chosen termination. When RSA patients were grouped according positive or negative antibodies, it was surprising to find that decidual CD4+ CXCR5+ PD-1+ ICOS+ memory Tfh cells significantly increased in RSA patients with positive antibody compared to RSA patients with negative antibody. However, the percentages of CD4+ CXCR5+ PD1+ CCR7- memory Tfh cells did not change in the deciduas of the two groups. Circulating and decidual B cells significantly increased in antibody-positive RSA patients compared with antibody-negative RSA patients. Correlation analysis indicated a strong association between the decidual CD4+ CXCR5+ PD-1+ ICOS+ memory Tfh cells and B cells in antibody-positive RSA patients. These new findings provide unique insights into memory Tfh cells in mediating feto-maternal immune tolerance.

Multiple antibody detection in 'seronegative' myasthenia gravis patients.

Myasthenia gravis (MG) is an autoimmune disease caused by antibody mediated impairment in the neuromuscular junction. Seronegative MG (SNMG) without antibodies against acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) by routine assays accounts for about 20% of all MG patients. Plasma from 81 Chinese MG patients previously found to be seronegative was tested by routine assays for AChR and MuSK antibodies. These samples were screened by (i) a novel, highly sensitive radioimmunoassay for AChR antibodies; (ii) cell-based assays for clustered AChR, MuSK and lipoprotein receptor-related protein 4 (LRP4) antibodies; (iii) a radioimmunoassay for titin antibodies. Antibodies to AChR, MuSK, LRP4 and titin were found in 25% (20/81), 4% (3/81), 7% (6/81) and 6% (5/78) of SNMG patients, respectively. In total, 37% of SNMG patients were found to be positive for at least one of the tested antibodies. AChR antibody positive patients had more severe disease (P = 0.008) and a trend towards fewer remissions/minimal manifestations than AChR antibody negative patients. The four patients with coexistence of antibodies had more severe disease, whilst the seronegative patients had milder MG (P = 0.015). Detection of multiple muscle antibodies by more sensitive assays provides additional information in diagnosing and subgrouping of MG and may guide MG treatment.

The relation between ischemia modified albumin level and autoimmunity/chronic inflammation in celiac disease

Abstract Objective We established an expectation that ischemia-modified albumin (IMA) levels are higher in the celiac disease since it is an autoimmune/chronic inflammatory disease. In this study, we determined the level of IMA and its relation to autoimmunity/chronic inflammation in celiac disease. Material and methods The level of IMA of 65 patients diagnosed with celiac disease and 65 healthy volunteers, was measured with the serum ELISA kit. C-reactive protein (CRP), anti-gliadin antibodies immunoglobulin A (AGA-lgA), anti-gliadin antibodies immunoglobulin G (AGA-lgG), anti-tissue transglutaminase immunoglobulin A antibodies (Anti-t-TGA), anti-tissue transglutaminase immunoglobulin G antibodies (Anti-t-TGG) levels were studied. Results IMA (30.8 ng/mL vs. 20.1 ng/mL, p=0.006; respectively) levels in celiac patients were higher than the control group. In celiac patients who were antibody positive, IMA level was found to be higher compared to antibody negative patients. A positive correlation was determined between IMA level and AGA-IgA (r=0.504, p&lt;0.001), AGA-IgG (r=0.445, p&lt;0.001), Anti-t TGA (r=0.485, p&lt;0.001), Anti-t TGG (r=0.477, p&lt;0.001) and CRP (r=0.385, p=0.011) levels. Conclusion Chronic inflammation and autoimmunity were found to be associated with high levels of IMA. To use IMA as a diagnosis and follow-up criterion in celiac disease, IMA levels must be compared before and after treatment of active celiac disease.

The Current Status of Renal Transplant Recipients with Hepatitis C: A Single Center Experience

Renal transplantation (RTx) may result in the development of liver disorder/hepatic cancer or hepatitis C virus (HCV)- related membranoproliferative glomerulonephritis, which may lead to graft loss, in renal failure patients with previously untreated HCV infection. Long-term survival is longer in HCV antibody-positive renal transplant recipients than in HCV antibody-negative/-positive dialysis patients, whereas renal graft survival and patient survival are lower in HCV antibody-positive renal transplant recipients than in HCV antibody-negative patients; thus, HCV treatment should be administered to HCV antibodypositive renal transplant recipients. Interferon/ribavirin (IFN/Rib) therapy is one of the current HCV treatments in Japan. In renal failure patients including those undergoing hemodialysis, Rib is contraindicated because of possible kidney function problems; IFN monotherapy is indicated for these patients. However, in clinical practice, IFN monotherapy is not performed adequately because of efficacy problems or adverse reactions to IFN, leading to the presence of many HCV carriers and patients with previous HCV infection among hemodialysis patients in the RTx waiting list. The sustained virological response in patients receiving IFN therapy after RTx is low. Many patients discontinue the therapy and some develop graft loss because of IFN-related acute rejection. Therefore, dialysis patients with HCV infection who are scheduled for RTx should first receive IFN therapy. In Japan, daclatasvir/ asunaprevir combination therapy was introduced as an IFN-free antiviral therapy in September 2015. However, its safety in dialysis patients has not been established, and these patients still require IFN therapy. We report the current state of renal transplant recipients with HCV at our hospital.