Antibody-negative Patients Research Articles

Abstract A008: Discriminant function for predicting survival of lung adenocarcinoma patients developed by using immune parameters of PD-L1, Gal-9, and XAGE1 expression on tumor cells and T cell infiltration score

Abstract Purpose: XAGE1 is a cancer/testis antigen and expressed in ~40% of advanced lung adenocarcinomas. Antibody response to XAGE1 was frequently observed in those patients. Furthermore, CD4 and CD8 T-cell responses against XAGE1 could be frequently detected in antibody positive patients. The overall survival (OS) of XAGE1 antibody-positive patients was prolonged significantly compared to the antibody-negative patients. Thus the XAGE1 immune response appeared to be involved in the patient prognosis. In this study, we studied other immune regulation mechanisms than XAGE1 immunity in lung adenocarcinoma patients. We found positive and negative involvement of PD-L1 and Gal-9, respectively, for patient prognosis. Based on the findings, we developed a discriminant function capable of efficiently predicting the patient prognosis using those immune parameters. Experimental Design: XAGE1, PD-L1 and Gal-9 expression in lung cancer was investigated using tissue microarray (TMA) including 194 adenocarcinomas, 112 squamous cell carcinomas, 17 small cell carcinomas, and 11 others, and 32 metastatic lung tumors by IHC. Tumor infiltrating lymphocytes were analyzed by automated scan scope. Clinical relevance of XAGE1, PD-L1, Gal-9 expression on tumor cells, and tumor infiltrating lymphocytes was evaluated in lung adenocarcinoma patients. Results: Frequency of PD-L1, Galectin-9 and XAGE1 expression on lung adenocarcinoma was 49.0%, 31.4% and 27.8%, respectively. OS of the patients with high PD-L1 expressing tumors was prolonged compared to the patients with low/- expressing tumors. On the other hand, OS of the patients with high Galectin-9 or XAGE1 expressing tumors was shortened compared to the patients with low/- expressing tumors. OS of the patients with high T cell infiltration in the tumor was prolonged compared to the patients with low/- T cell infiltration. By using the parameters including PD-L1, Gal-9 and XAGE1 expression on tumor cells, and CD4 and CD8 T-cell infiltration score in the tumor, we developed a discriminant function capable of efficiently predicting overall survival in lung adenocarcinoma patients Conclusions: OS of the lung adenocarcinoma patient was clearly predictable using the discriminant function developed using the immune parameters including PD-L1, Gal-9 and XAGE1 expression on tumor cells, and CD4 and CD8 T-cell infiltration score in the tumor independently from TNM classification. The findings suggested the involvement of PD-1/PD-L and Tim-3/ Gal-9 pathways of immune regulation, and of XAGE1 immune response, in the tumor microenvironment for prognosis of the lung adenocarcinoma patients. Those parameters are useful as biomarkers. Citation Format: Yoshihiro Ohue, Kurose Koji, Mikio OKa, Eiichi Nakayama. Discriminant function for predicting survival of lung adenocarcinoma patients developed by using immune parameters of PD-L1, Gal-9, and XAGE1 expression on tumor cells and T cell infiltration score. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A008.

Diagnosis and surgical indications of oxyphilic follicular tumors in Japan: Surgical specimens and cytology.

Oxyphilic cell carcinoma is a relatively rare type of differentiated thyroid carcinoma. We investigated the diagnosis of oxyphilic cell carcinoma based on surgical specimens and cytology to elucidate the indications for surgery for oxyphilic tumors. Among 330 patients pathologically diagnosed as having an oxyphilic cell carcinoma or adenoma, the incidence of carcinoma was 21%. The pathological diagnosis of oxyphilic cell carcinoma was related to tumor size (>4 cm). On cytology, 79% of the tumors were classified as category IV or greater by the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), but no significant difference was established between category IV or greater and categories I-III regarding the incidence of carcinoma. Of 998 patients cytologically diagnosed as having oxyphilic cell tumors (BSRTC category IV), 426 underwent surgery and 66 (15%) were diagnosed as malignancies. In a univariate analysis, serum thyroglobulin (Tg) levels (>500 ng/dL) for anti-Tg antibody-negative patients, tumor size (>4 cm) and US class (≥3) significantly predicted malignant histology. A multivariate logistic analysis revealed that US finding was an independent predictor of malignant histology, and tumor size (>4 cm) also predicted malignancy when the Tg level was excluded from the variables. These findings suggest that, for thyroid tumors diagnosed as oxyphilic follicular neoplasms on cytology, surgical indications are tumors with US class ≥3, tumor size >4 cm, and Tg >500 ng/dL (with negative Tg-antibody). It is not appropriate to perform surgery for all cases for a precise histological classification, unlike the BSRTC recommendation.

The impact of angiotensin II type 1 receptor antibodies on post-heart transplantation outcome in Heart Mate II bridged recipients.

Antibodies targeting angiotensin II type 1 receptor (AT1R) have been associated with malignant hypertension, autoimmune diseases and acute rejection and graft loss in solid organ transplantation. The aim of our study was to assess the impact of anti-AT1R antibodies on survival and incidence of acute cellular rejection (ACR) and pathology antibody-mediated rejection (pAMR) in a population of heart transplant recipients who were bridged to transplantation with a durable mechanical assist device Heart Mate II. Sera of 69 consecutive heart transplant recipients transplanted between October 2008 and August 2014 were tested for the presence of angiotensin II type 1 receptor antibodies before Heart Mate II device implantation and at the time of transplantation. Overall survival and post-transplant rejection-free survival were compared between antibody-negative and antibody-positive recipients using Kaplan-Meier and log-rank tests. Anti-AT1R antibodies were present in 8 patients (11.6%) before Heart Mate II implantation. During the left ventricular assist device (LVAD) bridging, 44 patients (63.8%) who were initially anti-AT1R antibody-negative became positive, leaving 17 (24.6%) anti-AT1R antibody-negative patients at the time of transplantation for all comparisons. One- and 5-year survival was 88 ± 8 and 76 ± 10% for anti-AT1R antibody-negative and 87 ± 5 and 81 ± 7% for anti-AT1R antibody-positive patients, respectively (P = 0.582). Freedom from ACR at 1 year was 68 ± 12% for anti-AT1R-negative and 75 ± 6% for anti-AT1R-positive recipients (P = 0.218). None of the anti-AT1R-negative patients developed AMR 1 year post-transplantation, whereas freedom from pAMR in anti-AT1R-positive recipients was 98 ± 2% (P = 0.198). Our data showed no difference in the overall post-heart transplant survival and freedom from acute cellular and antibody-mediated rejection between anti-AT1R-negative and anti-AT1R-positive recipients. Further research is needed to assess the role of anti-AT1R antibodies in the risk stratification of LVAD-bridged recipients on the post-heart transplantation outcomes.

Is There a Role for Anti-Neutrophil Antibody Testing in Predicting Spontaneous Resolution of Neutropenia in Young Children

▪Immune neutropenia is the most common referral to pediatric hematologists. Controversy exists as to whether anti-neutrophil antibody testing is necessary or helpful in establishing a diagnosis, predicting outcomes or establishing the necessity of treatment with G-CSF. It is also unclear if clinicians can separate immune neutropenia and hereditary/congenital neutropenia based on patients' clinical presentations, blood counts and anti-neutrophil antibody testing.We reviewed the records of 60 patients with the clinical diagnosis of autoimmune or idiopathic neutropenia, enrolled in the Severe Chronic Neutropenia International Registry (SCNIR) who had the onset of neutropenia before age 2 and who were tested for anti-neutrophil antibodies (positive or negative) to see if they resolved neutropenia by age 7 years. We identified 36 antibody positive and 24 antibody negative patients. Neutropenia resolved by age 7 in 27/36 (75%) antibody positive and in 15/24 (62.5%) antibody negative patients (p = 0.3910, Fisher's exact test). The median age at recovery for those with resolving neutropenia was 3.10 years for the antibody positive and 3.60 years for antibody negative patients (mean ages 3.39 and 3.52 years, respectively; p = 0.7614, unpaired t-test). All 60 patients had severe neutropenia (mean ANC 0.376 x 109/L ± 0.620, median 0.193 x 109/L) and history of recurrent fevers and infections, and were treated with G-CSF (mean dose antibody positive 3.12 ± 7.22 mcg/kg/day, mean dose antibody negative 2.57 ± 3.21 mcg/kg/day, p = 0.7311, unpaired t-test; median doses 1.42 and 1.53 mcg/kg/day, respectively). The ANC responses were quite similar, with antibody positive patients' mean ANC on treatment 3.36 x 109/L ± 1.48; antibody negative mean ANC on treatment 4.10 x 109/L ± 2.06 (p = 0.107, unpaired t-test; median ANCs 1.83 and 2.42 x 109/L, respectively). There were no apparent differences in demographic or hematological characteristics of the patients that resolved or failed to resolve.We also identified 8 children with ELANE mutations who had a positive test for anti-neutrophil antibodies. A positive anti-neutrophil antibody result is generally thought to predict a benign course and favor withholding treatment with G-CSF. Six of eight of these children did not receive G-CSF until after the development of severe infections, which included pneumonia, liver abscess, and cellulitis, including one who developed severe cellulitis with the loss of a lower extremity. Importantly, neutropenia did not resolve in any of the ELANE mutated patients.This retrospective review demonstrates that anti-neutrophil antibody testing in young children is of very limited or perhaps no value in predicting prognosis or response to G-CSF treatment. Furthermore, the results of the antibody testing may lead to withholding G-CSF therapy from children who are at risk of severe infectious complications. We believe it is prudent to treat young children with severe neutropenia who have recurrent fevers and infections independent of the anti-neutrophil antibody test results. We also advocate genetic testing to detect congenital neutropenia and predict outcomes in these patients. DisclosuresBoxer:Amgen: Equity Ownership. Dale:Amgen: Consultancy, Honoraria, Research Funding.

Hepatitis C Virus (HCV) Infection among Seronegative Patients undergoing Haemodialysis in a Remotely Located Tertiary Care Hospital of Northern India: Value of HCV-RNA and Genotypes.

Haemodialysis (HD) patients are at an increased risk of Hepatitis C virus (HCV) infection, which is significantly associated with increased morbidity and mortality. The aim of this study was to find the prevalence of HCV infection in anti-HCV antibody negative haemodialysis patients by Real-time PCR (RT-PCR) and value of HCV-RNA among seronegative patients undergoing haemodialysis in a remotely located tertiary care hospital. A total of 100 chronic renal failure patients on haemodialysis were studied. All the patients were screened for anti-HCV antibodies by ELISA test and for HCV-RNA by RT-PCR. The overall prevalence of HCV infection was 32%. Antibody positivity was 30% and HCV-RNA by RT-PCR was detected in 20%. HCV-RNA in seronegative patients was detected in 2.8%. Serological assays (30%) are quite reliable for detecting HCV infection in patients undergoing haemodialysis in our tertiary care hospital. Only a small proportion of them (2.8%) require the documentation of viral genome for current infection.

Clinical Characteristics of Anti-3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Antibodies in Chinese Patients with Idiopathic Inflammatory Myopathies.

ObjectiveThe objective of this study was to detect the prevalence of anti-3-hydroxyl-3- methylglutaryl coenzyme A reductase (anti-HMGCR) antibodies in Chinese patients with idiopathic inflammatory myopathies (IIMs), and to analyze the clinical features of the antibody-positive IIM patients.MethodsThe presence of anti-HMGCR antibodies was detected in 405 patients with IIMs, 90 healthy controls, and 221 patients with other rheumatic diseases by using an ELISA kit. Clinical data from anti-HMGCR antibody-positive and -negative patients were compared. Long-term follow-up of the anti-HMGCR antibody-positive patients was conducted to evaluate the role of anti-HMGCR antibody in IIM disease prognosis.ResultsOf the 405 IIM patients, 22 (5.4%) were found to carry the anti-HMGCR antibody. These IIM patients were predominantly female (73%), and only 3 anti-HMGCR antibody-positive patients with IIM were exposure to statins. Most patients experienced progressive onset, and presented with muscular weakness. Dysphagia was observed in half of the patients (p < 0.01), and 15% of these patients experienced the complication of interstitial lung disease (ILD) (p > 0.05). Mean creatine kinase (CK) levels were higher in antibody-positive patients than in antibody-negative patients (p < 0.05). Muscle biopsies were available from 12 anti-HMGCR antibody-positive patients, eight who experienced myofiber necrosis and showed very little or no evidence of inflammatory cell infiltrates in their muscle biopsies. Of these eleven patients who were followed-up 2.5- to 29-month, 73% experienced improvement after treatment. A cross-sectional study showed that anti-HMGCR antibody levels were significantly associated with CK levels (r = 0.486, p = 0.026) as well as with Myositis Disease Activity Assessment (MYOACT) scores (r = -0.67, p = 0.003) during the initial visit. However, changes in serum anti-HMGCR antibody levels did not correlate with changes in CK levels, Manual Muscle Testing 8 (MMT-8) scores or MYOACT scores in long-term follow-up.ConclusionThe major clinical features of anti-HMGCR antibody-positive Chinese IIM patients were muscle weakness and dysphagia, which were seen in patients with and without statin exposure. This subtype of patients were responsive to immunosuppressive treatment and received good prognoses after treatment, but serum levels of the anti-HMGCR antibody do not correlate with disease activity.

Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy.

ObjectiveTo investigate anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsSera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain–Barré syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti-NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti-NF155 antibodies referred from other clinics were enrolled for clinical characterization.ResultsThe positivity rate for anti-NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti-NF155 antibodies. No anti-NF155 antibody carriers had anti-NF186 antibodies. Anti-NF155 antibody-positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F-wave latencies than anti-NF155 antibody-negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti-NF155 antibody-positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti-NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti-NF155 antibody-positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did.InterpretationAnti-NF155 antibodies occur in a subset of CIDP patients with distal-dominant involvement and symmetric nerve hypertrophy.

Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial

ObjectivesTo examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year...

Drug trough levels predict therapeutic responses to dose reduction of adalimumab for rheumatoid arthritis patients during 24 weeks of follow-up.

To evaluate the impact of adalimumab (ADA) dose-halving on therapeutic responses and drug levels, the differences in drug levels among patients with different therapeutic responses and the optimal baseline cut-off ADA levels for predicting persistent remission or low disease activity (LDA) at week 24 of dose-halving therapy in 64 RA patients who had already achieved LDA or remission at baseline. Anti-ADA antibody levels were determined by bridging ELISA, ADA levels were evaluated using sandwich ELISA and therapeutic responses were assessed by the 28-joint DAS change. The optimal cut-off drug levels for predicting persistent remission were determined by receiver operating characteristic curve analysis. At baseline, 25 (39.1%) and 39 (60.9%) patients had achieved remission and LDA, respectively. After 24 week ADA dose-halving, persistent remission was observed in 23 patients, remission turned LDA in 2 patients, persistent LDA in 24 patients and disease flare in 15 (23.5%) patients. Three patients who developed anti-ADA antibodies at week 24 of dose-halving had very low drug levels and disease flare. Among 61 anti-ADA antibody-negative patients, ADA levels declined by half after 24 weeks of dose-halving (median 5.5 vs 2.6 μg/ml). Baseline ADA levels were significantly higher in patients with persistent remission (median 10.5 μg/ml) or LDA (4.5 μg/ml) than in those with disease flare (0.9 μg/ml), indicating associations of ADA levels with therapeutic responses. An ADA level above the cut-off value of 6.4 μg/ml might predict persistent remission after dose-halving with high sensitivity and specificity. ADA dose-halving is feasible for patients who have achieved remission and sufficient drug levels. Drug level monitoring may help clinicians optimize the dosing regimen and prevent overtreatment for patients receiving anti-TNF-α therapy.

Spontaneous remission of proteinuria is a frequent event in phospholipase A2 receptor antibody-negative patients with membranous nephropathy.

Phospholipase A2 receptor antibodies (PLA2R-Ab) and thrombospondin type-1 domain-containing 7A antibodies (THSD7A-Ab) are present in 70-80% of patients with membranous nephropathy (MN). Little, however, is known about the pathogenesis of MN and the clinical outcome in PLA2R-Ab- and THSD7A-Ab-negative patients. In this prospective multicentre observational study, the clinical outcome of 37 patients with biopsy-proven MN who were negative for PLA2R-Ab and THSD7A-Ab in the serum was analysed. A total of 198 patients were screened for inclusion in the study. Of these, 157 patients were positive for PLA2R-Ab and 4 patients for THSD7A-Ab. The remaining 37 patients were negative for both antibodies were and included in this study. Six patients died during the follow-up, five because of malignant diseases and one of an infection. One patient went into end-stage renal disease, and two patients were lost to follow-up. The remaining 28 patients were followed for at least 24 months (35.6 ± 8.9 months). Seventeen patients received immunosuppressive (IS) therapy, and 11 received supportive care only. At the end of the follow-up, 14 of the 17 patients treated with immunosuppressants and 10 of 11 patients on supportive therapy had a remission of proteinuria. The time to reach remission of proteinuria and serum creatinine levels at the end of the follow-up were not different between both groups. A univariate Cox regression analysis indicated that the use of immunosuppression did not alter the chance to reach a remission of proteinuria. A high number of PLA2R-Ab- and THSD7A-Ab-negative patients with MN have a good prognosis and might not need IS therapy.

HCV F protein amplifies the predictions of IL-28B and CTLA-4 polymorphisms about the susceptibility and outcomes of HCV infection in Southeast China

Cytotoxic T lymphocyte associated antigen-4(CTLA-4) is an inhibitory receptor with great value in the progression of hepatitis C virus (HCV) infection related diseases. To determine the potential associations of IL-28B rs12979860 and CTLA-4 rs231775, rs3087243 and rs5742909 polymorphisms with the generation of HCV F protein, susceptibility and outcomes of HCV infection, a total of 375 healthy controls, 219 HCV spontaneous recovered patients and 600 chronic HCV patients from Southeast China were recruited and genotyped in this study. And the relative mRNA levels of CTLA-4 in T cells were detected. Logistic regression analysis showed that rs231775 A allele was associated with significantly higher rate of spontaneous viral clearance in anti-HCV F antibody negative patients (adjusted OR=0.512, P=0.008), but allele A was related to higher mRNA level of CTLA-4 with the generation of HCV F protein. And rs5742909 T allele added up to the risk of HCV infection chronicity significantly in patients with the presence of HCV F protein (adjusted OR=2.698, P=0.003). Also, the rs5742909 CC genotype, along with the presence of HCV F protein, indicated a significantly higher CTLA-4 level than that in anti-HCV F antibody negative patients. The AG+AA genotype of rs3087243 significantly increased the susceptibility to HCV infection in subjects over 56years old (adjusted OR=1.595, P=0.011). Genotype–genotype interaction between IL-28B rs12979860 and CTLA-4 rs3087243 was found to be significantly associated with increased susceptibility to HCV infection (adjusted OR=1.509, P=0.005). Haplotype analysis in CTLA-4 also showed significant association with the generation of HCV F protein. All these results indicated the importance of IL-28B and CTLA-4 polymorphisms and their associations with HCV F protein in the risk and chronicity of HCV infection in Chinese Han population in Southeast China.

Enteroviruses and Type 1 Diabetes: Candidate Genes Linked With Innate Immune Response

In addition to HLA associated genetic predisposition, the role of exogenous factors in the development of type 1 diabetes (T1D) is well admitted. Since many decades, accumulating evidence strongly has supported an association between enteroviruses (EV) and T1D (Hober and Sauter, 2010). Moreover, the potential mechanisms underlying this enteroviral pathogenesis are getting better understood, and may also be linked to background susceptibility.

Association of antithyroid peroxidase antibody with fibromyalgia in rheumatoid arthritis

To investigate how autoimmune thyroiditis (ATD) affects the clinical presentation of established rheumatoid arthritis (RA) with particular reference to fibromyalgia and chronic widespread pain (CWP). A cohort of 204 patients with RA for whom the presence or absence of autoimmune thyroid antibodies was documented was examined for the relationships between thyroid autoantibodies and fibromyalgia or CWP. We identified 29% who tested positive for antithyroid peroxidase antibodies (TPOAb). The anti-thyroglobulin antibody (TgAb) was found in 24%. Among the thyroid autoantibody-positive patients, 40% had a diagnosis of fibromyalgia or CWP versus 17% for antibody negative patients. Logistic regression analyses (adjusted by age, sex, diabetes and BMI) indicated that TPOAb-positive patients were more likely to have fibromyalgia or CWP, with an odds ratio (OR) of 4.641, 95% confidence interval (CI) (2.110-10.207) P<.001. Adjusting for spinal degenerative disc disease did not change the association with fibromyalgia, OR 4.458, 95% CI (1.950-10.191), P<.001. The OR between TgAb and fibromyalgia was not significant (P>.05). Additional logistic regression analyses (adjusted by age, sex and BMI) indicated a significant relationship between TPOAb and fibromyalgia or CWP in patients without diabetes and those without hypothyroidism (OR of 4.873, 95% CI (1.877-12.653), P=.001 and OR of 4.615 95% CI (1.810-11.770), P=.001, respectively). There may be a positive association between the ATD antibody TPOAb, and fibromyalgia syndrome and CWP in patients with established RA.

Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis.

ObjectiveTo investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.MethodsA total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.ResultsAmong patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.ConclusionPharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.

Effectiveness of and risk associated with aspirin therapy in hemodialysis patients with a background of antiplatelet factor 4/heparin complex antibody detection

BackgroundThe optimal prevention measures against hemodialysis (HD)-associated complications, including all-cause thrombotic events and death, are unclear. MethodsThis prospective study was designed to assess the effect of aspirin on prevention of HD-associated complications. Patients were divided into four groups according to platelet factor-4/heparin-complex (PF4/H) antibody detection and aspirin prescription: Group 1, antibody(−)/aspirin(+); Group 2, antibody(−)/aspirin(−); Group 3, antibody(+)/aspirin(+); and Group 4, antibody(+)/aspirin(−). Adverse events were compared among all four groups. Cox hazard regression was performed to analyze the effects of anti-PF4/H antibody and aspirin on thrombosis and death. ResultsThis study included 648 patients undergoing HD; 142 were positive for anti-PF4/H antibodies, and 229 had received aspirin before enrollment. During the 4-year follow-up period, 138 patients developed thrombosis, and 63 of these events were anti-PF4/H antibody-associated. A total of 112 patients died; 75 died of coronary heart disease (CHD). Group 4 had a significantly higher incidence of total and anti-PF4/H antibody-associated thrombosis events as well as total and CHD-associated death than did the other three groups. Aspirin had a preventive effect against all adverse events in anti-PF4/H antibody-positive patients, but not in antibody-negative patients. Group 1 patients with baseline D-dimer levels of <0.6μg/mL developed more hemorrhagic events than did patients in the other groups. ConclusionsAspirin prevention of thrombosis and death in patients undergoing HD might require consideration of the anti-PF4/H antibody status. In antibody-positive individuals, taking aspirin could improve the prognosis and therefore might be recommended. In antibody-negative individuals, prevention was minimal and the bleeding risk was obviously increased; thus, aspirin should be avoided or at least require careful evaluation prior to aspirin treatment.

Serum antinuclear antibody may be associated with less severe disease activity in neuromyelitis optica.

Antinuclear antibody-positive multiple sclerosis (MS) patients have shorter disease duration and lower Expanded Disability Status Scale (EDSS) scores. The aim of this study was to compare clinical and laboratory features between MS and neuromyelitis optica (NMO) patients with and without autoantibodies and to investigate the prognosis of NMO in patients with and without autoantibodies. The frequencies of antinuclear, anti-Sjögren's syndrome A (SSA)/Ro, anti-Sjögren's syndrome B (SSB)/La and anti-thyroid peroxidase (TPO) antibodies in the sera of 75 NMO patients and 131 MS patients were compared. Clinical and laboratory profiles were also compared between NMO patients with and without autoantibodies, including annual relapse rate and time from onset of NMO to EDSS scores of 4.0 (limited walking but without aid) and 6.0 (walking with unilateral aid). More NMO than MS patients had antinuclear and anti-SSA/Ro antibodies (31% vs. 10%, P<0.001, and 21% vs. 3%, P<0.001, respectively). Antinuclear antibody-positive NMO patients had a lower annual relapse rate from disease onset to serum sampling compared with antinuclear antibody-negative NMO patients, independent of treatment regimen. Antinuclear antibody-negative NMO patients reached an EDSS score of 6.0 earlier than antinuclear antibody-positive NMO patients (P=0.026). Cerebrospinal fluid cell counts were higher in anti-SSA/Ro-positive than in anti-SSA/Ro-negative NMO patients. More anti-TPO antibody-positive than anti-TPO antibody-negative NMO patients had oligoclonal immunoglobulin G bands (60% vs. 11%, P=0.048). Autoantibodies possibly modulate the pathophysiology of NMO. Antinuclear antibody may be associated with less severe disease activity or less disability in NMO.

Population pharmacokinetic analysis of certolizumab pegol in patients with Crohn's disease.

Certolizumab pegol (CZP), an anti–tumor necrosis factor α agent, is an effective therapy for Crohn's disease (CD). A population pharmacokinetic (PK) analysis of subcutaneously administered CZP was performed using data from 2157 CD patients from 9 separate studies. The aim was to determine which covariates influence the disposition of CZP. The final CZP population PK model consisted of a baseline, first‐order absorption, and 1‐compartment disposition. CZP antibodies were treated as a structural model covariate and caused apparent clearance (CL/F) to increase from 0.685 to 2.74 L/day. Body surface area (BSA) influenced both CL/F and apparent volume of distribution (V/F) in a linear fashion; both parameters increased by more than 53% and 49%, respectively, across the range of BSA measurements in the data. Albumin influenced CZP CL/F in a nonlinear fashion; CL/F decreased from 1.05 to 0.613 L/day with increasing albumin concentrations in antibody‐negative patients. C‐reactive protein (CRP) had a borderline influence and CL/F increased by more than 20% across the range of CRP measurements in the data set. Race had a minor influence on V/F. The determined covariates' impact on CZP disposition may be of clinical utility in CZP therapy of CD patients when the PK/pharmacodynamic relationship becomes available.

Sonographic appearance of thyroid cancer in patients with Hashimoto thyroiditis.

To determine whether the sonographic appearance of thyroid cancer differs in patients with and without Hashimoto thyroiditis. Patients with histologically proven thyroid cancer who had thyroid peroxidase (TPO) antibodies measured and sonography performed preoperatively were included. We evaluated each nodule for size, echogenicity, composition, margins, halo, and vascularity and evaluated the background heterogeneity of the gland. There were 162 thyroid cancers in 145 patients. Forty-two patients (29.0%) had Hashimoto thyroiditis with positive TPO antibodies, and 103 patients (71.0%) had negative TPO antibodies. The background echogenicity was more often heterogeneous in TPO antibody-positive patients compared to those who had negative TPO antibodies (57.1% versus 26.2%; P= .0005). Comparing cancers in TPO antibody-positive to TPO antibody-negative patients, there was no significant difference in the size, echogenicity, composition, margins, halo presence, calcification presence and type, or vascularity of the cancerous nodule (P > .05). Among TPO antibody-positive patients, comparing thyroid cancerous nodules in patients with heterogeneous glands to those with homogeneous glands, there was no significant difference in any sonographic characteristic except the margin of the nodule, which was more often irregular or poorly defined in heterogeneous glands and more often smooth in homogeneous glands (P< .05). Sonographic features of thyroid cancer are similar in patients with and without Hashimoto thyroiditis. Among patients with Hashimoto thyroiditis and thyroid cancer, the sonographic appearance of the cancerous nodule is similar, except that cancerous nodule margins are more likely to be irregular or poorly defined when the gland is heterogeneous.

Membranous Nephropathy: The Journey Continues …

Membranous Nephropathy: The Journey Continues …

Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.

Objective:To determine whether myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) were predictive of a demyelination phenotype in children presenting with acquired demyelinating syndrome (ADS).Method:Sixty-five children with a first episode of ADS (12 acute disseminated encephalomyelitis, 24 optic neuritis, 18 transverse myelitis, 11 other clinically isolated syndrome) were identified from 2 national demyelination programs in the United Kingdom and France. Acute serum samples were tested for MOG-Abs by cell-based assay. Antibodies were used to predict diagnosis of multiple sclerosis (MS) at 1 year.Results:Twenty-three of 65 (35%) children had MOG-Abs. Antibody-positive and antibody-negative patients were not clinically different at presentation, but identification of MOG-Abs predicted a non-MS course at 1-year follow-up: only 2/23 (9%) MOG-Ab–positive patients were diagnosed with MS compared to 16/42 (38%) MOG-Ab–negative patients (p = 0.019, Fisher exact test). Antibody positivity at outset was a useful predictor for a non-MS disease course, with a positive predictive value of 91% (95% confidence interval [CI] 72–99), negative predictive value of 38% (95% CI 24–54), positive likelihood ratio of 4.02 (CI 1.0–15.4), and odds ratio of 6.5 (CI 1.3–31.3).Conclusions:MOG-Abs are found at presentation in 35% of patients with childhood ADS, across a range of demyelinating disorders. Antibody positivity can be useful in predicting a non-MS disease course at onset.