Ab-negative Patients Research Articles

Preventing kidney transplant failure by screening for antibodies against human leucocyte antigens followed by optimised immunosuppression: OuTSMART RCT

Design Investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Background Allografts in 3% of kidney transplant patients fail annually. Development of antibodies against human leucocyte antigens is a validated predictive biomarker of allograft failure. Under immunosuppression is recognised to contribute, but whether increasing immunosuppression can prevent allograft failure in human leucocyte antigen Ab+ patients is unclear. Participants Renal transplant recipients > 1 year post-transplantation attending 13 United Kingdom transplant clinics, without specific exclusion criteria. Interventions Regular screening for human leucocyte antigen antibodies followed, in positive patients by interview and tailored optimisation of immunosuppression to tacrolimus, mycophenolate mofetil and prednisolone. Objective To determine if optimisation of immunosuppression in human leucocyte antigen Ab+ patients can cost-effectively prevent kidney allograft failure. Outcome Time to graft failure after 43 months follow-up in patients receiving the intervention, compared to controls, managed by standard of care. Costs and quality-adjusted life-years were used in the cost-effectiveness analysis. Randomisation and blinding Random allocation (1 : 1) to unblinded biomarker-led care or double-blinded standard of care stratified by human leucocyte antigen antibodies status (positive/negative) and in positives, presence of donor-specific antibodies (human leucocyte antigen antibodies against donor human leucocyte antigen) or not (human leucocyte antigen antibodies against non-donor human leucocyte antigen), baseline immunosuppression and transplant centre. Biomaker-led care human leucocyte antigen Ab+ patients received intervention. Human leucocyte antigen Ab-negative patients were screened every 8 months. Recruitment Began September 2013 and for 37 months. The primary endpoint, scheduled for June 2020, was moved to March 2020 because of COVID-19. Numbers randomised From 5519 screened, 2037 were randomised (1028 biomaker-led care, 1009 to standard of care) including 198 with human leucocyte antigen antibodies against donor human leucocyte antigen (106 biomaker-led care, 92 standard of care) and 818 with human leucocyte antigens antibodies against non-donor human leucocyte antigen (427 biomaker-led care, 391 standard of care). Numbers analysed Two patients were randomised in error so 2035 were included in the intention-to-treat analysis. Outcome The trial had 80% power to detect a hazard ratio of 0.49 in biomarker-led care DSA+ group, > 90% power to detect hazard ratio of 0.35 in biomarker-led care non-DSA+ group (with 5% type 1 error). Actual hazard ratios for graft failure in these biomarker-led care groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54 to 1.74), respectively. There was 90% power to demonstrate non-inferiority of overall biomarker-led care group with assumed hazard ratio of 1.4: This was not demonstrated as the upper confidence limit for graft failure exceeded 1.4: (1.02, 95% CI 0.72 to 1.44). The hazard ratio for biopsy-proven rejection in the overall biomarker-led care group was 0.5 [95% CI: 0.27 to 0.94: p = 0.03]. The screening approach was not cost-effective in terms of cost per quality-adjusted life-year. Harms No significant differences in other secondary endpoints or adverse events. Limitations Tailored interventions meant optimisation was not possible in some patients. We did not study pathology on protocol transplant biopsies in DSA+ patients. Conclusions No evidence that optimised immunosuppression in human leucocyte antigen Ab+ patients delays renal transplant failure. Informing patients of their human leucocyte antigen antibodies status appears to reduce graft rejection. Future work We need a better understanding of the pathophysiology of transplant failure to allow rational development of effective therapies. Trial registration This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information.

Detection of Mycobacterium avium-intracellulare Complex (MAC) by Bronchial Lavage and the Relationship with Titers of Anti-Glycopeptidolipid-Core IgA Antibodies to MAC in Patients with Pulmonary MAC Disease.

Higher rates of diagnosis of pulmonary Mycobacterium avium-intracellulare complex (MAC) disease by bronchoscopy (BS) in patients who could not diagnose by sputum cultures have been suggested, but the detailed utility of BS, especially in combination with anti-glycopeptidolipid-core IgA antibodies (anti-MAC Ab), is still unclear. A total of 111 patients at our hospital with suspected MAC who underwent BS because they were sputum-negative from April 2018 to March 2022 were analyzed prospectively. These patients were also divided into two groups, anti-MAC Ab-positive and anti-MAC Ab-negative, and compared. A total of 111 patients underwent BS, though 95 (38.0%) of 250 enrolled patients were sputum smear/culture-positive. The age of the 111 patients was 69.14 (31.0-89.0) years, and 90 (81.0%) were female; 69 (62.2%) of 111 patients were either smear-positive (n = 42, 37.8%) or culture-positive (n = 27, 24.3%) by BS. Of the total 111 patients, 69 (62.2%) were anti-MAC Ab-positive and 57 (82.6%) of 69 patients were also positive by BS. In contrast, only 12 (28.6%) of the 42 anti-MAC Ab-negative patients were positive by BS. The sensitivity and specificity of anti-MAC Ab for positive by BS were 82.6% and 71.4%, respectively, and the area under the curve (AUC) on receiver-operating characteristic (ROC) curve analysis was 0.807. BS and anti-MAC Ab showed similar usefulness to confirm the diagnosis in patients who could not be diagnosed by sputum examination, but pulmonary MAC disease was strongly suspected based on chest radiography/CT findings. These two examinations were correlated, and their combination appeared to provide more accurate diagnosis and earlier therapy.

Characteristics of anti-transcriptional intermediary factor 1 gamma autoantibody-positive dermatomyositis patients in Singapore

This study aimed to determine the clinical profile and outcome of anti-transcriptional intermediary factor 1 gamma autoantibody (anti-TIF1-γ Ab)-positive dermatomyositis patients and propose cancer screening programmes based on regional cancer trends. Data on history, physical findings and investigations were collected using chart review on dermatomyositis patients seen at a tertiary hospital in Singapore from 1 January 2015 to 30 June 2021. Comparisons were made between anti-TIF1-γ Ab-positive and anti-TIF1-γ Ab-negative dermatomyositis. Ninety-six dermatomyositis patients were analysed and 36 patients were positive for anti-TIF1-γ Ab. Anti-TIF1-γ Ab-positive patients had more frequent heliotrope rashes, shawl sign, periungual erythema, holster sign, Gottron's papules, dysphagia and truncal weakness (P<0.05). They had less frequent interstitial lung disease, polyarthritis, cutaneous ulcers, palmar papules and mechanic's hands (P<0.05). After 48 months of follow-up, a higher proportion of anti-TIF1-γ Ab-positive patients developed cancer compared with Ab-negative patients (63.9% versus 8.5%; odds ratio 19.1, 95% confidence interval 6.1-59.8; P<0.001). Nasopharyngeal carcinoma (NPC) and breast cancer were the most common malignancies, followed by bowel, lung and non-Hodgkin lymphoma. Most malignancies (78.3%) occurred within 13 months prior to, or 4 months after the onset of dermatomyositis. The mortality rate for anti-TIF1-γ Ab-positive patients was significantly higher than Ab-negative patients (36.1% vs 16.7%, P=0.031), and Kaplan-Meier survival estimates at 24 months were 66% and 89%, respectively (P=0.0153). These observational data support periodic screening of NPC and other malignancies in patients with anti-TIF1-γ Ab-positive dermatomyositis in Singapore.

Rejection and graft outcomes in kidney transplant recipients with and without angiotensin II receptor type 1 antibodies

AimAngiotensin II type 1 receptor antibody (AT1R Ab) is a non-Human Leucocyte Antigen (HLA) antibody that is maybe associated with early severe kidney transplant rejection and worse graft outcomes. This study aimed to assess the association between AT1R Ab and kidney transplant rejection and graft outcomes. MethodsWe performed a retrospective analysis of all adult kidney transplant recipients in an Australian centre who had an AT1R Ab test between 1 January 2015 to 30 June 2020. AT1R Ab positive patients were compared to AT1R Ab negative patients. Primary outcomes were rejection risk, type and histopathological severity scores. Secondary outcomes were 8-week graft function and graft loss. ResultsOf 965 kidney transplants that were performed during the study period, 73 patients had AT1R Ab tested; 16 (22%) were positive and 57(78%) were negative. Positive patients were on average younger and had higher level of donor-specific HLA antibodies. Rejection occurred in 13 (81%) positive patients and 41 (72%) negative patients (P = 0.45). No significant differences in rejection type or severity were found. HLA mismatch and peak panel reactive antibody ≥80%, but not AT1R Ab, independently predicted rejection. Average (132 vs. 177 mmol/L, P = 0.302) and graft loss were not significantly different between groups. ConclusionThe study found no evidence that AT1R Ab is associated with rejection type, severity or worse graft function. Future studies should assess its relationship with graft outcomes to help complement immunological risk assessment and potentially provide therapeutic options to alter outcomes.

Predictors, Risk Factors and Outcomes of Patients with SAA with Anti-HLA Class I Antibodies Treated with Immunosuppressive Therapy

Introduction: Platelet refractoriness, defined as persistently inadequate post-transfusion count increments, can be immune or non-immune. Human leukocyte antigen (HLA) Class I antibodies are the usual immune cause. The presence of HLA platelet antibodies (Abs) in hematologic disease has been associated with poorer clinical outcomes, graft failure in hematopoietic stem cell transplant, increased bleeding, and decreased survival. In immune severe aplastic anemia (SAA), literature addressing prophylactic transfusion of platelets is lacking, but most recommend transfusion with bleeding at a count <10 or <20 K/ µL if febrile or during ATG (anti-thymocyte globulin) administration. Chronic platelet transfusion is a risk for development of HLA Abs; nevertheless, some chronically transfused patients do not become alloimmunized while others do so rapidly, even after a single platelet transfusion. We analyzed our SAA patients to document the rate of HLA alloimmunization and its possible association with disease characteristics and outcomes after immunosuppressive therapy (IST). Methods: Clinical records from 444 SAA patients treated at the NIH Clinical Center from 2000 to 2022 were retrospectively reviewed. Demographics included: age, sex, HLA Class 1 Abs status, platelet refractoriness, peripheral blood counts, PNH clone, treatment and relapse, evolution to myeloid malignancy or chromosome abnormality, and overall survival (OS). Patients were tested for HLA Abs if they met 1 or more of 3 clinical criteria: 1) history of HLA Abs; 2) history of or current platelet transfusion refractoriness; 3) work up for bone marrow transplantation. Clinical refractoriness was defined as lack of platelet increment of >5 K/µL or a corrected count increment (CCI) of >5 K/µL. Patient lacking evidence of refractoriness were presumed anti-HLA negative and not tested, and those that tested negative for HLA Ab were transfused platelets unmatched for any HLA antigens. Logistic regression was used to analyze associations between age, sex, blood counts, PNH clone, and disease severity, and Kaplan Meier curves and Cox proportional hazards model for survival. Data were analyzed using R, and p<0.05 was considered statistically significant. Results: Demographic data were collected for 444 patients (Table.1). HLA Ab testing was performed in 155 patients while 289 didn't meet criteria for testing. Of 444 patients, 99 (22%) tested positive for HLA Class 1 Abs. Seventy-three of 99 patients responded to HLA matched platelets, whereas, 17 remained refractory and for 9 data were unavailable. Univariate analysis predicted male sex to be protective against HLA Abs formation (OR=0.59,p= 0.02), while more severe disease (VSAA, OR= 2.51, p<0.001) and lower baseline blood counts predicted alloimmunization. Low platelet counts (p<0.001) were most significant followed by absolute reticulocyte (ARC) and absolute neutrophil counts (ANC) with p=0.005. PNH was not associated with refractoriness, although data were incomplete. Only HLA Class 1 Ab status and age, and sex were strong predictors of survival in both univariate and multivariate analysis. ANC, ARC, and disease severity were significant predictors of survival in the univariate but not multivariate model. Median time to relapse was 2.4 years with a relapse rate of 36% at median follow-up. Rate of relapse was 46% in alloimmunized patients vs.34% in the Ab negative group, but this difference was not statistically significant (p=0.2). OS for the entire cohort was 84% at median follow up 4 years; HLA Ab-negative patients had a significantly higher OS compared with positive (86% and 75% respectively; p = 0.02). Rates of clonal evolution were also higher in the HLA Ab positive group but not statistically significant (25% vs. 13%, p=0.08). Conclusions: We report a large cohort of IST-treated SAA patients, comparing outcomes with and without HLA alloimmunization. Although SAA patients are usually heavily transfused platelets, we observed a rate of HLA alloimmunization of 22%. OS was decreased in HLA alloimmunized patients. Presence of HLA ab and age were strong predictors of survival. ANC, ARC and disease severity were predictors of survival only in the univariate model. Relapse and clonal evolution may be increased when HLA Abs are present. Overall, the presence of HLA Abs is associated with poorer outcomes in SAA patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Dengue Disease with ABO RH Blood Group

Background: Dengue viral infection is a global public health issue. Several viral and other host factors are the contributed factors including the ABO blood group for transmission of dengue virus (DENV). ABO blood groups have been shown to involve in the intensity of DENV. This study aims to find the association ABO and Rh blood group with DENV infection. Methods: This cross-sectional study was conducted in tertiary care hospital. All DENV NS-1 positive patients were included irrespective of age and gender. The blood group of all DENV-infected patients was determined through ABO and Rh anti-sera (forward blooding grouping). Descriptive data were analyzed through SPSS and Microsoft Excel. Results: Among a total of 105 dengue-infected patients, male were 68 patients and female were 37 patients. The highest number of cases were found in the age group 21-30 years and 11-20 years. The predominant blood group was found A positive in dengue viral infected patients while AB negative blood group was found common in Rh negative blood groups. Conclusion: Blood group A positive and AB negative patients in Rh positive and Rh negative blood groups had more risk of dengue viral infection as compared to other blood groups. Further studies are necessary to find the severity of patients with different blood groups. Based on their differential distribution in the community and their correlation with mosquito performance, it can be deduced that the risk of contracting dengue infection differs with the ABO and Rh blood groups. Additional study is necessary to determine whether HLA, dengue serotype, and ABO are experimental/predictor factors, and whether certain blood subgroups are associated with a disproportionately higher risk of dengue virus infection. Keywords: Dengue viral infection, Serotype, Anti-A, Anti-B, Anti-D, ABO, Rh blood group

TPO antibody status prior to first radioactive iodine therapy as a predictive parameter for hypothyroidism in Graves' disease.

ObjectiveWe investigated whether a positive thyroid peroxidase antibody (TPO Ab) status before radioactive iodine (RAI) therapy in patients with Graves’ hyperthyroidism is a predictive factor for developing hypothyroidism post RAI.MethodsWe performed a retrospective study of patients with Graves’ hyperthyroidism with known TPO Ab status, receiving the first administration of RAI. Patients from four thyroid outpatient centres in Belgium receiving their first RAI therapy between the years 2011 and 2019 were studied. Clinical, laboratory, imaging, and treatment data were recorded from medical charts. Hypothyroidism and cure (defined as combined hypo- and euthyroidism) were evaluated in period 1 (≥2 and ≤9 months, closest to 6 months post RAI) and period 2 (>9 months and ≤24 months post RAI, closest to 12 months post RAI).ResultsA total of 152 patients were included of which 105 (69%) were TPO Ab-positive. Compared to TPO Ab-negative patients, TPO Ab-positive patients were younger, had a larger thyroid gland, and had more previous episodes of hyperthyroidism. In period 1, 89% of the TPO Ab-positive group developed hypothyroidism and 72% in the TPO Ab-negative group (P = 0.007). In period 2, the observation was similar: 88% vs 72% (P = 0.019). In the multivariate logistic regression analysis, a positive TPO Ab status was associated with hypothyroidism in period 2 (adjusted OR: 4.78; 95% CI: 1.27–20.18; P = 0.024). In period 1, the aOR was 4.16 (95% CI: 1.0–18.83; P = 0.052).ConclusionA positive TPO Ab status in patients with Graves’ hyperthyroidism receiving the first administration of RAI is associated with a higher risk of early hypothyroidism.

Diagnostic challenges in patients with temporal lobe seizures and features of autoimmune limbic encephalitis.

Consensus criteria for autoimmune limbic encephalitis (ALE) allow for a diagnosis even without neuronal antibodies (Abs), but it remains unclear which clinical features should prompt neuronal Ab screening in temporal lobe epilepsy patients. The aim of the study was to investigate whether patients with temporal lobe seizures associated with additional symptoms or signs of limbic involvement may harbor neuronal Abs, and which clinical features should prompt neuronal Ab screening in these patients. We identified 47 patients from a tertiary epilepsy center with mediotemporal lobe seizures and additional features suggestive of limbic involvement, including either memory deficits, psychiatric symptoms, mediotemporal magnetic resonance imaging (MRI) hyperintensities or inflammatory cerebrospinal fluid (CSF). Neuronal Ab testing was carried out at two independent reference laboratories (Bielefeld-Bethel, Germany, and Barcelona, Spain). All brain MRI scans were assessed by two reviewers independently. Temporal lobe seizures were accompanied by memory deficits in 35/46 (76%), psychiatric symptoms in 27/42 (64%), and both in 19/42 patients (45%). Limbic T2/fluid-attenuated inversion recovery signal hyperintensities were found in 26/46 patients (57%; unilateral: n=22, bilateral: n=4). Standard CSF studies were abnormal in 2/37 patients (5%). Neuronal Abs were confirmed in serum and/or CSF in 8/47 patients (17%) and were directed against neuronal cell-surface targets (leucine-rich glioma inactivated protein 1: n=1, contactin-associated protein-2: n=1, undetermined target: n=3) or glutamic acid decarboxylase in its 65-kD isoform (n=3, all with high titers). Compared to Ab-negative patients, those who harbored neuronal Abs were more likely to have uni- or bilateral mediotemporal MRI changes (8/8, 100% vs. 18/38, 47%; p=0.01, Fisher's exact test). In patients with temporal lobe seizures and additional limbic signs, 17% had neuronal Abs affirming ALE diagnosis. Mediotemporal MRI changes were found in all Ab-positive cases and had a positive likelihood ratio of 2.11 (95% confidence interval 1.51-2.95).

Hepatitis B virus infection among patients with Rheumatoid Arthritis in Suez Canal University Hospital

Background: About 350 million individuals are considered having hepatitis B virus (HBV) infections worldwide, and 6.8% of cases have been observed of a reactivation of HBV triggered by immunosuppressive medications. Due to HBV reactivation, biologic or non-biological Synthetic antirheumatic disease-modifying drugs may be involved. For rheumatologists, HBV infection is a big concern. Patients and Methods: A descriptive cross-sectional study was carried out at Rheumatology outpatient clinic at Suez Canal University Hospital, Ismailia, during the period from 22 of January to 30 of July 2020 and included 200 patients with a history of Rheumatoid Arthritis. Patients were asked about their demographics and possible risk factors, and blood samples were collected for detection of HBV markers. Results: Evidence of present or past HBV infection with positive anti-HBc was found in 12% of patients (n=24). Among them, 4 patients had Overt HBV infection with positive HBsAg (2%) and another 4 patients had Occult hepatitis B, with negative HBsAg and positive HBV DNA (2%). Regarding HBV vaccination status, we found that 4 patients (16.7%) of HBc Ab positive patients were vaccinated and 69 patients (39.2%) of HBc Ab negative patients were vaccinated. Conclusion: This research indicates that HBV among rheumatoid arthritis patients is comparatively prevalent. Moreover, HBV carriers experience rheumatological symptoms. Risk factors for HBV infection in patients with Rheumatoid Arthritis included history of needle stick injury, dental visits, and prior surgical procedures.

A comparison of disease burden and symptoms with age among CoVid-19 patients from data in a Florida clinic.

Our knowledge of the disease burden and symptoms with age in COVID-19 patients is limited. Therefore, it is of interest to document the clinical aspect of this association with respect to the disease. We used the data of 3363 patients enrolled with an urgent care clinic in Volusia county, Florida for this study. Data shows difference in age among COVID-19 antibody (Ab) - positive patients (48.3 years, 95% CI = 46.9,49.7 years) and Ab-negative patients (46.1 years, 95% CI = 45.4, 46.8 years). However, disease burden by age is not significant on average. Nonetheless, COVID-19 positive patients between 40-69-years of age experienced the highest burden of disease and highest average number of symptoms. Thus, COVID-19 disease burden and number of symptoms experienced were highest among the 40-69-year-old patients. Those above the populations mean age of 46.4 years old were more likely to test positive for COVID-19.

Abstract 6538: CMV-specific immuno-dysregulation in recurrent glioblastoma patients can be overcome with therapeutic vaccination which is associated with tumor response and overall survival benefits in a Phase I/IIA study

Abstract Numerous independent laboratories using several techniques have demonstrated cytomegalovirus (CMV) antigens in over 90% of glioblastoma (GBM) tumors. We initiated a phase I/IIA multicenter study designed to demonstrate safety and determine the most immunogenic dose of an enveloped virus-like particle (eVLP) vaccine expressing the CMV gB and pp65 antigens for treatment of recurrent GBM patients. In Part A of the trial, 6 patients in each of 3 different antigen dose cohorts were vaccinated monthly and followed until tumor progression, with PBMCs collected 2 weeks after each vaccination. Surprisingly, only 7/18 patients enrolled in Part A of the trial had baseline CMV-specific antibody (Ab) titers. This was unexpected given the documented high prevalence of CMV antigens in GBM tumor samples as well as epidemiological data demonstrating much higher CMV Ab seropositive rates in otherwise healthy individuals of a comparable age. In the low dose cohort, 4/6 patients had baseline CMV Ab titers. Of these 4 patients,vaccination boosted strong T cell responses in 2 patients (based on IFN-γ ELISPOT against CMV gB and pp65 antigens). Vaccination did not boost T-cell responses in the CMV Ab-negative patients. In the intermediate dose cohort, among 4 evaluable patients, T cell responses were robustly boosted in the only patient with a baseline CMV Ab titer. In marked contrast, the T-cell responses in the high dose cohort were boosted in 3/5 evaluable patients, all of which were CMV Ab seronegative at baseline. Moreover, the T-cell responses correlated with tumor responses (stable disease based on 2 or more stable MRI scans) as well as improved PFS and 6 month OS relative to vaccine non-responders. To further understand the apparent disconnect between baseline CMV Ab titers and vaccine-mediated impact on tumor and clinical responses, we developed a more sensitive flow cytometry-based assay which evaluated proliferating (Ki-67-positive) gB- and pp65-specific T cells within naïve, central memory (CD45RA-CCR7+) or effector memory (CD45RA-CCR7-) subsets. Among 2/3 tested vaccine responders evaluated thus far in the high dose cohort that were CMV Ab negative at baseline, high frequencies of effector memory cells (~2% total CD3+CD4+ T cells) against both the CMV pp65 and gB antigens were detected at baseline. Collectively, these data suggest that CMV-specific immune dysregulation exists in a substantial number of rGBM patients, which can be overcome with the appropriate dose of a CMV vaccine immunotherapeutic. Importantly, vaccine-mediated boosting of CMV immunity correlates with improved tumor response and clinical outcomes and warrants further confirmation. Citation Format: Tamara Berthoud, Felicia Deonarine, Spenser Ng Cheong Chung, Catalina Soare, Francisco Diaz-Mitoma, David E. Anderson. CMV-specific immuno-dysregulation in recurrent glioblastoma patients can be overcome with therapeutic vaccination which is associated with tumor response and overall survival benefits in a Phase I/IIA study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6538.

Evaluation of thyroid dysfunction in patients with nephrotic syndrome.

BackgroundThyroid and kidney are interdependent on each other in many ways for optimal functioning of either organs. Proteinuria causes urinary loss of thyroid hormones and thyroid binding globulins in substantial amount resulting in subclinical/overt hypothyroidism. Autoimmunity, which can attack both the organs simultaneously, may also contribute considerably to the abnormal functioning of both organs.Aims and objectivesTo study the effect of proteinuria on the thyroid function and its association with autoimmunity.MethodsThe study was carried out on a total number of 60 patients with nephrotic range proteinuria attending the kidney and dialysis clinic PGIMS, Rohtak, India. Thyroid profile and baseline investigations along with Anti-TPO antibodies and renal biopsy were carried out on each patient. Patients were allocated to 2 groups based on Anti TPO antibody results: group A comprising 25 Anti-TPO Ab positive patients and group B comprising 35 Anti-TPO Ab negative patients.ResultsGroup A patients with Anti TPO antibody positivity had more elevated TSH levels (p<0.0001), proteinuria (p=0.0011) and serum creatinine (p=0.0137) as compared to group B patients. Group A patients had more diminished eGFR (p=0.0127) and serum albumin (p=0.0056) than patients in group B. TSH levels were positively correlated with proteinuria r=0.55 (p<0.0001, 95% CI 0.35 to 0.70) and serum creatinine levels r=0.56 (p<0.0001, 95% CI 0.36 to 0.71). TSH levels were negatively correlated with serum albumin levels r=−0.52 (p<0.0001, CI −0.68 to −0.31) and glomerular filtration rate r=−0.54 (p<0.0001, CI −0.69 to −0.33). On histopathology, membranous nephropathy - 29 out of 60 patients, 48% - was the most common finding in both the groups.ConclusionsNephrotic range proteinuria leading to thyroid dysfunction is a common entity but the association with autoimmunity causes an exaggerated effect on both these organs. Our study established a significant correlation between thyroid autoimmunity and nephrotic syndrome. Thus, a high index of suspicion should be kept in all patients with nephrotic syndrome to look for any associated antibodies against thyroid antigens. Autoimmunity causes more proteinuria and more elevations of thyrotropin leading to clinical hypothyroidism; however, the occurrence of overt hypothyroidism necessitating treatment needs further study.

The irreversible HCV-associated risk of gastric cancer following interferon-based therapy: a joint study of hospital-based cases and nationwide population-based cohorts.

Background:Hepatitis C virus (HCV) infection causes many extrahepatic malignancies; whether it increases gastric cancer risk and the risk reverses after anti-HCV therapy remain elusive.Method:A nationwide population-based cohort study of Taiwan National Health Insurance Research Database (TNHIRD) was conducted. In parallel, the risk factors and HCV-core-protein expressions were surveyed in gastric cancer patients from a tertiary care center.Results:From 2003 to 2012, of 11,712,928 patients, three 1:4:4, propensity-score-matched TNHIRD cohorts including HCV-treated (7545 patients with interferon-based therapy ⩾ 6 months), HCV-untreated (n = 30,180), and HCV-uninfected cohorts (n = 30,180) were enrolled. The cumulative incidences of gastric cancer [HCV-treated: 0.452%; 95% confidence interval (CI): 0.149–1.136%; HCV-untreated: 0.472%; 95% CI: 0.274–0.776%; HCV-uninfected: 0.146%; 95% CI 0.071–0.280%] were lowest in HCV-uninfected cohort (p = 0.0028), but indifferent between treated and untreated cohorts. HCV infection [hazards ratio (HR): 2.364; 95% CI: 1.337–4.181], male sex (HR: 1.823; 95% CI: 1.09–3.05) and age ⩾ 49 years (HR: 3.066; 95% CI: 1.56–6.026) were associated with incident gastric cancers. Among 887 (males: 68.4%; mean age: 66.5 ± 12.9 years, 2008–2018) hospitalized gastric cancer patients, HCV Ab-positive rate was 7.8%. None of the investigated factors exhibited different rates between HCV Ab-positive and Ab-negative patients. No HCV-core-positive cells were demonstrated in gastric cancer tissues.Conclusions:HCV infection, male sex and old age were risk factors for gastric cancer development. HCV-associated gastric cancer risk might be neither reversed by interferon-based therapy, nor associated with in situ HCV-core-related carcinogenesis.

Pediatric Neuromyelitis Optica Spectrum Disorders

Neuromyelitis optica spectrum disorders (NMOSDs) are a group of inflammatory and demyelinating disorders of the central nervous system that can occur in children and adults. The classic presentation of NMOSD is characterized by optic neuritis and transverse myelitis, but other presentations are also recognized, expanding the disease as NMO spectrum disorders. The purpose of this review is to discuss the clinical features, along with management and treatment options, including potential future therapeutic options, in pediatric NMOSD. The aquaporin-4 antibody (AQP4 ab) is specific for NMOSD; however, recently another antibody, the myelin oligodendrocyte glycoprotein (MOG ab) has been found in a subset of AQP4 ab-negative patients including in children. Most treatment studies are reported in adults, but retrospective studies on efficacy and safety of mycophenolate mofetil, azathioprine, and rituximab in pediatric NMOSD are available. While some pediatric NMOSD-specific treatment studies are available, more research is needed in the mechanisms of early onset and specific treatment options in children, including whether different treatment considerations are needed for AQP4 ab as opposed to MOG ab-positive disease.

A Role for Thiopurine Metabolites in the Synergism Between Thiopurines and Infliximab in Inflammatory Bowel Disease.

Interactions between principal cytotoxic thiopurine metabolites, that is 6-thioguanine nucleotides [6-TGN], and infliximab [IFX] and anti-IFX antibodies [Abs] may contribute to higher effectiveness of IFX-thiopurine combination therapy than monotherapies in inflammatory bowel disease. To examine if thiopurine metabolites influenced trough IFX and anti-IFX Abs, 89 patients previously assessed for anti-IFX Abs were included. To assess if IFX influenced thiopurine metabolites, eight patients who had responded to 12 weeks of intensified IFX at a constant thiopurine dosing were included. In the first cohort, IFX-thiopurine combination therapy reduced anti-IFX Ab detection [8/40; 20%] as compared with IFX monotherapy [22/49; 45%], odds ratio [OR] 0.31 [0.12-0.80], p < 0.05. 6-TGN was significantly lower in anti-IFX Ab-positive patients (50 pmol/8 × 108 red blood cells [RBC] vs 105, p < 0.01). All anti-IFX Ab-positive patients had 6-TGN < 117 pmol/8 × 108 RBC (sensitivity 100% [63-100], specificity 47% [29-65], area under the curveROC = 0.82, p < 0.01). Trough IFX was similar between anti-IFX Ab-negative patients in IFX monotherapy and IFX-thiopurine combination therapy [5.1 μg/mL vs 4.9, p = 0.76]. 6-TGN and IFX did not correlate [rP = 0.04, p = 0.83; rS = 0.02, p = 0.89, respectively]. In the second cohort, trough IFX increased during IFX intensification [ΔIFX median 6.5 μg/mL, p = 0.02], but 6-TGN was stable [6-TGN at Weeks 0, 4, 8, 12: 90 pmol/8 × 108 RBC, 93, 101, 90; p > 0.05]. Methylated mercaptopurine metabolite associations were consistently negative. Superior effect of IFX-thiopurine combination therapy over monotherapies partly relates to decrease in anti-IFX Abs, which associates with 6-TGN levels and has a lower therapeutic threshold than during thiopurine monotherapy. Additional benefit likely ascribes to synergy between different anti-inflammatory modes of action rather than direct drug interactions.

Histopathologic changes in anti-angiotensin II type 1 receptor antibody-positive kidney transplant recipients with acute rejection and no donor specific HLA antibodies

ObjectiveTo determine the association of antibodies against angiotensin II type 1 receptor (AT1R Ab) and histopathologic changes seen in patients with kidney allograft rejection and negative donor specific HLA antibodies (DSA). MethodsStored sera from 27 patients who had biopsy-proven rejection in the absence of DSA were tested for AT1R Ab. Biopsy slides of all patients were re-examined and classified according to Banff 2013 criteria. Histopathologic changes were compared between AT1R positive and negative patients. Results75% of patients with positive pre-transplant AT1R Ab had antibody mediated rejection (AMR) compared to 37% of AT1R Ab-negative patients. A trend towards increased interstitial inflammation was observed in the AT1R Ab positive group (p=0.08). More patients in the AT1R Ab positive group had microcirculation inflammation (88% vs 58% with glomerulitis scores ≥1; 75% vs 58% with peritubular capillaritis scores ≥1). ConclusionIn kidney transplant recipients with rejection and no DSA, a higher incidence of AMR and worse inflammation scores are observed in the presence of positive pre-transplant AT1R antibodies.

P.3.024 - Cardiovascular reactions to psychosocial stress and abuse history in patients with mood and anxiety disorders

We have conducted a 26-month-long comparative study involving young patients (2–6 years old) with a clinical diagnosis of spastic equinus secondary to cerebral palsy who have been treated with BoNT/A (BOTOX®, Allergan) tri-annually or annually. Serum samples were obtained to determine the presence or absence of blocking antibodies (Abs) by a mouse protection assay (MPA) and levels of anti-BoNT/A Abs by radioimmune assay (RIA). HLA DQ alleles were typed using blood samples to determine the possible association of certain HLA type(s) with the disease or with the Ab status. Blocking Abs were detected in only two out of 18 serum samples of the tri-annual group, but none were found in 20 samples of the annual group. The MPA-positive serum samples gave in RIA significantly higher anti-BoNT/A Ab-binding levels than the MPA-negative samples. On the other hand, when two MPA-positive sample data were excluded, serum samples from tri-annual and annual groups showed similar anti-BoNT/A Ab levels. Linkage of the disorder with a particular HLA DQA1 and DQB1 allele types was not observed due to the small sample size. However, by combining results with other studies on BoNT/A-treated Caucasian patients with cervical dystonia (CD), we found that, among Caucasian patients treated with BoNT/A, DQA1*01:02 and DQB1*06:04 were higher in Ab-positive than in Ab-negative patients. The genetic linkage was on the threshold of corrected significance.

Antibody responses to botulinum neurotoxin type A of toxin-treated spastic equinus children with cerebral palsy: A randomized clinical trial comparing two injection schedules

We have conducted a 26-month-long comparative study involving young patients (2–6years old) with a clinical diagnosis of spastic equinus secondary to cerebral palsy who have been treated with BoNT/A (BOTOX®, Allergan) tri-annually or annually. Serum samples were obtained to determine the presence or absence of blocking antibodies (Abs) by a mouse protection assay (MPA) and levels of anti-BoNT/A Abs by radioimmune assay (RIA). HLA DQ alleles were typed using blood samples to determine the possible association of certain HLA type(s) with the disease or with the Ab status. Blocking Abs were detected in only two out of 18 serum samples of the tri-annual group, but none were found in 20 samples of the annual group. The MPA-positive serum samples gave in RIA significantly higher anti-BoNT/A Ab-binding levels than the MPA-negative samples. On the other hand, when two MPA-positive sample data were excluded, serum samples from tri-annual and annual groups showed similar anti-BoNT/A Ab levels. Linkage of the disorder with a particular HLA DQA1 and DQB1 allele types was not observed due to the small sample size. However, by combining results with other studies on BoNT/A-treated Caucasian patients with cervical dystonia (CD), we found that, among Caucasian patients treated with BoNT/A, DQA1*01:02 and DQB1*06:04 were higher in Ab-positive than in Ab-negative patients. The genetic linkage was on the threshold of corrected significance.

Suspected antibody negative autoimmune limbic encephalitis: outcome of immunotherapy.

Whether and when to immunologically treat epilepsy patients with suggested autoantibody (AB)-negative limbic encephalitis (LE) is clinically challenging. Therefore, we evaluated the clinical outcome and eventual outcome predictors of immunotherapy in a group of AB-negative patients with recent-onset temporal lobe epilepsy (TLE), magnetic resonance imaging (MRI) indicators of LE, subjective cognitive decline, and/or psychiatric symptoms. This retrospective, observational, uncontrolled study monitored 28 TLE patients with suggested AB-negative LE along with methylprednisolone immunotherapy. All patients had seizures, amygdala and/or -hippocampal enlargement, subjective cognitive decline and/or behavioral problems. Eighty-six percent (24/28) were impaired in executive or memory functions, 39% (10/25) depressed, 81% were on antiepileptic drugs when pulse therapy started. After a median follow-up of 18 months, 46% (13/28) of the patients were seizure free (>2 months), 48% (13/27) showed MRI improvements (amygdala and/or hippocampal volume reduction), cognition improved in 57% (16/28), worsened in 32% (9/28), mood improved in 14% (4/25), and deteriorated in 11% (3/25). Immunotherapy was discontinued in 75% (21/28). Clinical changes did not correlate to each other. Outcomes could not be predicted. Immunological treatment of suggested AB-negative LE showed reasonable seizure control, MRI and cognitive improvements. Treatment success was not predictable from clinical features, nor definitely attributable to immunological treatment. Lacking biomarkers for the reliable diagnosis of AB-negative LE, we suggest that in presence of mild manifestations, and after initiating antiepileptic drug therapy, negative dynamics in MRI, seizures, cognition, and behavior should be documented before immunosuppressive treatment is initiated.

Differential Effect of Viral Hepatitis Infection on Mortality among Korean Maintenance Dialysis Patients: A Prospective Multicenter Cohort Study.

The role of infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in terms of survival among dialysis patients remains incompletely understood. In the present multicenter prospective cohort study, we investigated the prevalences of HBV and HCV infection among 3,321 patients receiving maintenance dialysis in Korea, and assessed the impacts of these infections on survival. All included patients underwent hepatitis B antigen (HBsAg) and HCV antibody (Ab) testing, which revealed that 236 patients (7.1%) were HBsAg-positive, and 123 patients (3.7%) were HCV Ab-positive. HBsAg-positive and HCV Ab-positive patients were matched to hepatitis virus-negative patients using a propensity score at a ratio of 1:2. The prevalences of HBV and HCV infection did not significantly differ according to dialysis modality. Linear-by-linear association analysis revealed that hepatitis B prevalence significantly increased with increasing dialysis vintage (p = 0.001), and hepatitis C prevalence tended to be higher with increasing dialysis vintage (p = 0.074). We compared the survival of HBsAg-positive and HCV Ab-positive patients to that of hepatitis virus-negative patients. After propensity score matching, cumulative survival did not differ between HBsAg-positive and HBsAg-negative patients (p = 0.37), while HCV Ab-positive patients showed significantly lower survival than HCV Ab-negative patients (p = 0.03). The main conclusions of the present study are that HBV infection prevalence increased with longer dialysis vintage, and that both HBV and HCV infections were most prevalent among patients with the longest dialysis vintage. Additionally, HCV infection among maintenance dialysis patients is associated with an increased risk of mortality.