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Background To determine the thyroid uptake rate by correcting the background and analyse its clinical significance. Methods The study included 161 patients with hyperthyroidism. The thyroid uptake rate was calculated by drawing a 100 pixels ROI (Region of Interest) background, above and below the thyroid and correcting the thyroid ROI for background counting. At the same time, the clinical baseline characteristic parameters such as age and thyroid volume etc. of patients with hyperthyroidism were collected. The consistency of 9mTcO4uptake rate before treatment and 131I-uptake rate after treatment, and the correlation between uptake rate of thyroid and baseline characteristic parameters were also analysed. Results The uptake rate of 99mTcO4 was found positively correlated with 3 h-RAIU, 24 h-RAIU, 3 h/24 h conversion rate, thyroid volume, 131I activity FT3 and FT4, and showed negative correlation with age, effective half-life. (P＜0.05). The uptake rate of 131I was found positively correlated with 3 h-RAIU, 24 h-RAIU, 3 h/24 h conversion rate, thyroid volume, 131I activity, FT3, FT4. (P＜0.05). In patients with positive thyrotrophin receptor antibody (TRAb), a significant positive correlation between uptake rate of 99mTcO4 and 131I (P＜0.05) was observed. There was a high consistency between pre-treatment uptake rate of 99mTcO4 and post-treatment uptake rate of 131I (P = 0.009; W = 0.7). Conclusions The corrected thyroid uptake rate is remarkably correlated with clinical characteristic parameters of patients, which can be used to comprehensively evaluate the comprehensive condition of patients with hyperthyroidism. more...

ZusammenfassungDie Riesenzellarteriitis (RZA) ist in der Altersgruppe der über 50-Jährigen die häufigste idiopathische systemische Vaskulitis. Die Erkrankung bedarf einer zeitnahen Diagnostik und Therapie, um schwere Komplikationen wie eine Erblindung oder einen Schlaganfall zu vermeiden. Die Rezidivneigung erfordert eine mehrjährige, zum Teil lebenslange Glukokortikoid(GC)-Therapie, was das Risiko GC-induzierter Langzeitnebenwirkungen erhöht. Daher wird bei der Mehrzahl der Patienten eine additive GC-einsparende Therapie empfohlen. Hierzu steht der Anti-IL-6-Rezeptor-Antikörper Tocilizumab in subkutaner Applikation als zugelassene Substanz zur Verfügung, alternativ kann Methotrexat (MTX) eingesetzt werden (off-label). more...

ObjectiveTo investigate the association between changes in anti-acetylcholine receptor antibody (AChR Ab) levels induced by immunosuppressive treatment and myasthenia gravis (MG) prognosis at 1-year post-treatment in patients with MG.MethodsWe included 53 consecutive AChR Ab-positive patients with MG whose AChR Ab levels were remeasured within 100 days of initiating immunosuppressive treatment (median remeasuring time post-treatment: 71 (55–84) days). The AChR Ab level reduction rate (RR-AChRAb, %/day) adjusted for the time between treatment initiation, and AChR Ab level remeasurement was calculated as follows: (pretreatment–post-treatment AChR Ab level)/pretreatment AChR Ab level/days between therapy initiation and AChR Ab level remeasurement ×100. Participants were divided into two groups based on the cut-off value of RR-AChR Ab, determined using receiver operating characteristic analyses for achieving minimal manifestation (MM) or better status at 1-year postimmunosuppressive treatment. The Myasthenia Gravis Foundation of America postintervention status and MG activity of daily living (MG-ADL) score at 1-year post-treatment were compared between the two groups.ResultsThe RR-AChRAb cut-off value was 0.64%/day. The high RR-AChRAb group had a higher ratio of MM or better status (90% vs 65%, p=0.03) and lower MG-ADL score (median; 1 vs 2, p=0.04) than the low RR-AChRAb group. Kaplan-Meier analyses showed the early MM achievement in the high RR-AChRAb group (p=0.002, log-rank test).ConclusionsHigh RR-AChRAb is associated with a favourable outcome at 1-year post-treatment. AChR Ab remeasurement within 100 days of therapy may be useful for predicting AChR Ab-positive MG outcomes at 1-year post-treatment. more...

The diagnostic criteria for N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis require the presence of CSF antibodies against the NMDAR, whereas serum antibodies are considered specific only if accompanied by CSF antibodies. Current assays include in-house immunochemistry (IHC), or cell-based assays (CBA) which use live (L-CBA) or fixed cells (F-CBA), and commercially available fixed-cells CBA (C-CBA), but these have not been compared in parallel. We compared the L-CBA with F-CBA, C-CBA, and IHC using sera and CSFs archived from > 30,000 received for testing and previously positive by L-CBA. Referring neurologists, if identified, provided “definite” or “unlikely” diagnoses of NMDAR-Ab encephalitis for 31 paired serum-CSF samples and 53 unpaired sera. There was good concordance between paired sera and CSFs, with 13/16 “definite” pairs positive, and 7/8 “unlikely” pairs negative in all in-house assays. In unpaired “definite” sera, L-CBA was most sensitive. However, 19/24 serum samples from “unlikely” patients were positive by L-CBA, with only 5/24 and 1/24 positive by F-CBA and IHC, respectively. In available samples, C-CBA demonstrated high sensitivity for CSF, but surprisingly low sensitivity for serum. Overall, regardless of the technique, CSF results were accurate and easy to interpret, but if CSF is unavailable, negative serum C-CBA results in cases with suspected NMDAR-Ab encephalitis could be repeated by a more sensitive in-house assay. Although these assays are sensitive, particularly for CSF, referral of sera with low pre-test probability should be avoided to reduce clinically-irrelevant “false positive” results. more...

Small-molecule detection in an immunoassay format generally employs competition or labeling. A novel direct-detection label-free primary immunoassay utilizing second harmonic generation (SHG) has been developed and the utility of the method has been demonstrated for several small-molecule narcotics. Specifically, the binding of morphine, methadone, and cocaine to antimorphine, antimethadone, and anticocaine antibodies was measured by SHG, allowing binding affinities and rates of dissociation to be obtained. The SHG primary immunoassay has provided the first kinetic measurements of small-molecule hapten interactions with a receptor antibody. The kinetics reveal for the first time that competitive immunoassays achieve their selectivity by taking advantage of the kinetics of association and dissociation of the labeled and unlabeled target and nontarget small-molecule to the capture antibody. In particular, the induced fit of the target small-molecule to their antibody pairs prolongs their residence time, while the nontarget small-molecule dissociate rapidly in comparison. more...

Objective We investigated the effectiveness of tocilizumab (an anti-interleukin-6 receptor antibody) in patients with polymyalgia rheumatica (PMR). Methods We performed a systematic literature review from the inception dates until August 7, 2019 for articles reporting tocilizumab administration to treat isolated PMR. Results We identified 59 patients with isolated PMR treated with tocilizumab. All studies used intravenously administered tocilizumab at a dose of 8 mg/kg monthly. Tocilizumab monotherapy was administered to 24 and combination therapy (tocilizumab + glucocorticoid) to 35 patients. Tocilizumab monotherapy achieved low disease activity scores in only 17% of patients at week 4 and in only 71% patients even at week 12. Compared to glucocorticoid monotherapy, the reduction in the cumulative glucocorticoid dose was between 58% and 70% using a combination of tocilizumab and glucocorticoids, and 33–100% of the patients eventually showed glucocorticoid-free remission. All relapses occurred in patients administered tocilizumab monotherapy. No new safety event was reported. Conclusion Tocilizumab is effective in cases of isolated PMR, particularly in combination with glucocorticoids. In addition to its glucocorticoid-sparing effect, it achieves glucocorticoid-free remission and reduces relapse rates. Tocilizumab monotherapy is not recommended. more...

Objective To ascertain the phenomenological characterisation of catatonia in N-methyl- d -aspartate receptor antibody encephalitis (NMDAr-AbE). Methods A systematic review of case reports was undertaken in accordance with PRISMA guidelines. Case reports of NMDAr-AbE containing sufficient information on the cases' clinical presentation and meeting the study's inclusion criteria were selected. Cases were searched for clinical data in keeping with core catatonic signs by applying the screening instrument of the Bush-Francis Catatonia Rating Scale. When two or more core signs were ascertained catatonia was considered to be present. Results 2645 records were identified through the database search. Following screening and application of eligibility/inclusion criteria 139 articles were selected reporting on 189 individual subjects. Catatonia was present in 60% of these cases. The most prevalent signs were immobility/stupor (70%), mutism (67%), excitement (50%), posturing/catalepsy (34%), stereotypies (31%), and rigidity (30%). Immobility/stupor and excitement co-occurred in the same patient in 33% of cases. Conclusion The phenomenological profile of catatonia in this sample of cases of NMDAr-AbE was characterised by a preponderance of signs in the hypokinetic spectrum. However, excitement often co-occurred in these patients suggesting that fluctuations in catatonic semiology may be frequent. more...

Myasthenia gravis and thymoma are often presented in association with ∼10% of myasthenic cases having concomitant thymoma. Thymic carcinoma is one of the rarest/aggressive human epithelial tumors and has no correlation with myasthenia gravis hitherto. Here is provided a clinical case and review of literature on a very rare association of thymic carcinoma (with no sign of thymoma) and myasthenia gravis (antiacetylcholine receptor antibody positive). Two years after thymectomy, clinical evolution was satisfactory. This clinical case elicits hypothesis that thymic carcinoma may be related with myasthenia gravis, what may have good prognostic from oncologic and neurologic perspectives. more...

Objectives Polymyalgia rheumatica (PMR) is a systemic inflammatory disease in the elderly of unknown etiology. While glucocorticoids are the mainstay of treatment for PMR, various glucocorticoid-related adverse events are common. Recently, several studies have reported the efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, for PMR treatment in addition to an accompanying reduction, or even tapering-off, of glucocorticoids in some cases. The objective of this study was to elucidate the efficacy of TCZ monotherapy in the absence of glucocorticoids for PMR. Method We conducted a 2-year, prospective, single-center, open-label pilot study of TCZ monotherapy in patients with PMR. TCZ (8 mg/kg) was administered at fortnightly intervals for the first 2 months and monthly over the next 10 months. Subsequently, patients were observed for another year without any treatment. The primary endpoints were the remission rates at weeks 12 and 52, and the secondary endpoints were the relapse rate and safety over the total 104 weeks. Results Thirteen patients were included in this study. Four of these patients achieved remission at week 12 (remission rate 31%). Four patients withdrew from the study due to adverse events (n = 2) and inefficacy (n = 2). At week 52, all 9 patients who had completed the first year achieved remission. Eight patients completed the drug-free second year, with 7 maintaining remission. Conclusions TCZ monotherapy is well tolerated and can lead to remission in most patients with PMR in the absence of glucocorticoids. more...

Background The incidence of myasthenia gravis (MG) is increasing, and its characteristics in elderly patients are believed to differ from those in younger patients. However, only a few studies have focused on elderly patients with MG. Objective To review the characteristics of MG in elderly patients and evaluate whether older age is an independent factor associated with achieving minimal manifestation status (MMS). Methods This retrospective cohort study included 367 patients (319 non-elderly and 48 elderly patients) with MG enrolled at Xiangya Hospital from September 1, 2016, to December 31, 2018. We collected demographic data and information regarding comorbidities, antibody status, Myasthenia Gravis Foundation of America classification, affected muscle groups, thymoma, and treatment. MMS was defined as the primary outcome. Results Comorbidities were more common in elderly than in younger patients with MG. Anti-acetylcholine receptor antibody was the dominant subtype, whereas anti-muscle-specific tyrosine kinase antibody was rare and detected only in non-elderly patients. Elderly patients were more likely than younger patients to have generalized MG, but the frequency of thymoma was lower (28.5% vs. 10.4%, p = 0.0078). MMS or better was achieved in 154 (48.3%) and 13 (27.1%) non-elderly and elderly patients, respectively. Older age did not appear to be an independent factor associated with MMS (hazard ratio = 0.625; 95% confidence interval, 0.345-1.131). Conclusions Older age was not an independent factor for a worse prognosis in patients with MG. The treatment of elderly patients with MG should be individually tailored. more...

Background and Aims Primary membranous nephropathy (MN) is a glomerulus-specific autoimmune disorder caused by anti-phospholipase A2 receptor (anti-PLA2R) antibodies in 70-80% of cases. We sought to investigate the utility of anti-PLA2R antibody as a non-invasive screening method for the diagnosis of primary MN in patients with nephrotic syndrome (NS). Method A total of 203 consecutive patients with NS admitted in the Nephrology Department of Fundeni Clinical Institute, Bucharest, Romania, between January 2015 and December 2019 were screened for anti-PLA2R antibodies by an ELISA assay (Euroimmun, Lubeck, DE). A positive anti-PLA2R serology was defined as an ELISA value over 2 RU/ml. Subsequently, all patients underwent kidney biopsy to confirm the histological diagnosis. Results Of the 203 patients with NS, 113 (55.7%) patients tested negative for anti-PLA2R antibodies, while 23 (11.3%) and 67 (33%) patients had an anti-PLA2R antibody titer of 2-20 RU/ml and >20 RU/ml, respectively. Mean age and serum creatinine of the entire cohort were 53 ± 13 years and 1.84 ± 1.63 mg/dl, respectively, while median 24-h proteinuria was 6.8 g/day (IQR: 4.8 – 10.6). Thirty patients (14.7%) were identified to have a potential secondary cause of NS. Ninety-five patients (46.8%) had a histological diagnosis of MN, while 108 patients were diagnosed with other glomerular disorders. In patients with anti-PLA2R antibody titer > 20 RU/ml, the most frequent histological diagnosis was MN (n=61, 91%) with 6 patients having other glomerular patterns of injury (two FSGS, one minimal-change disease, one membrano-proliferative glomerulonephritis, one diabetic nephropathy and one postinfectious glomerulonephritis) (Figure 1). Of patients with intermediate anti-PLA2R antibody titer (2-20 RU/ml), 39% had MN and 61% had other glomerular disorders (Figure 1). Eighteen patients with MN had a positive work-up for secondary causes, eight patients (44%) having an anti-PLA2R antibody titer > 20 RU/ml. Additionally, patients with anti-PLA2R antibody titer > 20 RU/ml had a lower serum creatinine (1.5 ± 0.89 mg/dl) than patients with intermediate titer (1.89 ± 1.21 mg/dl) and those with negative titer (2.03 ± 1.98 mg/dl) (Figure 2). When analyzing the diagnostic performance of anti-PLA2R antibodies in the entire cohort we identified an AUC of 0.83 (95%CI, 0.78-0.89; p Conclusion Serum anti-PLA2R antibody screening in patients with NS is a useful method for the diagnosis of primary MN. In younger patients (less than 60 years-old) that have a preserved renal function and a negative work-up for secondary causes a positive anti-PLA2R antibody test highly predicts a diagnosis of primary MN. more...

Introduction Anti-NMDA receptor encephalitis in an acute form generally presents with abnormal movements and psychiatric symptoms. Therapeutic plasma exchange has been considered to be one of the first line treatment options. This report highlights the role of plasma exchange in anti-NMDA receptor encephalitis in pediatric patients. Methods This is a retrospective analysis of four cases of a severe form of encephalitis due to anti-NMDA receptor antibody. All these four patients were evaluated for clinical and laboratory profile before plasma exchange. Plasma exchange was performed with Cobe Spectra Version 7.0(Terumo BCT, USA), and 5% albumin and fresh frozen plasma were used as replacement fluid. Results A total of 20 procedures (range: 2–8/patient) were performed on four patients on an alternate day basis. Slow recovery and long-term hospitalization (range: 25–70 days) was observed in all these patients and may be due to delayed initiation of plasma exchange. One patient was lost in follow up while another one had fatal consequences after one month of discharge from the hospital. Conclusion Early diagnosis and timely initiation of therapeutic plasma exchange along with immunosuppressive therapy hasten the recovery, duration of hospitalization and yield a better outcome. more...

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CAS Article PubMed Google Scholar Download references Unite de preparation et de controle pharmaceutique (UPCP), Centre Hospitalier de Brive La Gaillarde, 1 boulevard du Dr Verlhac, 19312, Brive la Gaillarde Cedex, France Caroline Streicher & Annick Daulange Medecine interne et Maladies infectieuses, Centre Hospitalier de Brive La Gaillarde, 1 boulevard du Dr Verlhac, 19312, Brive la Gaillarde Cedex, France Xavier Engalenc, Marion Gaudin, Guillaume Vignaud & Bruno Abraham You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar Correspondence to Caroline Streicher. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector. The authors declare that they have no conflict of interest. Due to the case report nature of the study, the consent of the Ethics Committee of CH de Brive was not required. Patient data collection were performed in accordance of the Declaration of Helsinki. The patient consent was obtained to publish the data. All data generated and analysed during this case report are included in this manuscript. All authors... more...

Catatonia is a psychomotor dysregulation syndrome of diverse aetiology, increasingly recognised as a prominent feature of N-methyl-d-aspartate receptor antibody encephalitis (NMDARE) in adults. No study to date has systematically assessed the prevalence and symptomatology of catatonia in children with NMDARE. We analysed 57 paediatric patients with NMDARE from the literature using the Bush-Francis Catatonia Rating Scale. Catatonia was common (occurring in 86% of patients), manifesting as complex clusters of positive and negative features within individual patients. It was both underrecognised and undertreated. Immunotherapy was the only effective intervention, highlighting the importance of prompt recognition and treatment of the underlying cause of catatonia. more...

Over the last months, pandemic SARS‐CoV‐2 caused a significant challenge for clinicians. Unfortunately, no approved and validated treatments are available. Intravenous tocilizumab, an antirheumatic drug, seems to be promising in counteracting cytokine storm caused by SARS‐CoV‐2 infection with associated clinical improvements. We report herein a case series of patients with COVID‐19 pneumonia who were treated with tocilizumab administrated, for the first time, subcutaneously with good clinical and radiological outcomes. This article is protected by copyright. All rights reserved. more...

A 69-year-old woman presented with acute bilateral ptosis, ophthalmoplegia, ataxia, and hyporeflexia in the extremities following an antecedent upper respiratory infection. We suspected that she had Miller Fisher syndrome (MFS) and performed an edrophonium test (ET) to rule out myasthenia gravis (MG). Edrophonium chloride improved the patient's bilateral ptosis, but not her ophthalmoplegia. Given the absence of the waning phenomenon on electrophysiological examination, the anti-acetylcholine receptor antibody, and a diurnal variation of symptoms, we concluded that the ET result was a false-positive. A diagnosis of MFS was confirmed by the presence of a positive anti-GQ1b antibody. To our knowledge, this is the first case report of MFS with a false-positive ET. more...

Introduction Myasthenia gravis (MG) crisis has no specific reported correlation with atrial fibrillation (AF). We present a series of patients observed from a single general neurologist's outpatient and inpatient practice over a 9-year period who experienced the combination of MG crisis and AF. Case report Retrospective chart review of patients within 1 neurologist's inpatient and outpatient practice was done. Charts were selected based on the occurrence of newly diagnosed AF during MG crisis over a 9-year period. Most patients were diagnosed in the hospital and then followed as outpatients. Charts were reviewed to determine factors that may have played a role in the co-occurrence of these 2 conditions. Eight patients were identified that had co-occurring MG crisis and AF. All patients had very active MG, and were in or had recently been in MG crisis at the time their AF was discovered. Patients tended to have late-onset MG to be male, to be acetylcholinesterase receptor antibody positive, and to have improvement or remission of their AF once the MG achieved better clinical control. Conclusion New-onset AF can occur during MG crisis. The cardiac outcome improves with treatment of the underlying disease, after initial cardiac stabilization. more...

IL-6 contributes significantly to the chronic inflammatory process of rheumatoid arthritis (RA). Tocilizumab, a humanized anti-human IL-6 receptor antibody that blocks the signaling originated by the IL-6/IL-6R complex, is an effective treatment. However, predictors of the response to tocilizumab are still required. We aimed to combine IL-6 and soluble IL-6R (sIL-6R) levels to identify groups of responses.Heparinized blood and clinical data from 63 RA patients were collected before treatment and after 3 and 6 months. Two-step clustering (SPSS v.18) was used to establish the relationship between IL-6 and sIL-6R. Then, we compared European League Against Rheumatism (EULAR) response criteria with remission achievement in the groups of patients.Three statistical significant clusters of RA patients (i.e., g1, g2, and g3) were defined by serum concentrations of IL-6 and sIL-6R at baseline. All groups of RA patients had higher IL-6 and sIL-6R levels than healthy donors. The levels of IL-6 expressed as median (IQR) in g1 patients were 124(90-183)pg/ml, in g2 12.3(4.4-24)pg/ml, and in g3 60.1(30-146)pg/ml (p0.001). The levels of sIL-6R expressed as mean ± sd in g1 patients were 250.5 ± 72ng/ml, in g2 269.1 ± 125ng/ml, and in g3 732.7 ± 243ng/ml (p0.001). Disease activity score (DAS)28, C-reactive protein, and erythrocyte sedimentation rate were comparable in the three groups at baseline. Disease duration in g3 was the longest (median(IQR) years: g1 = 11(5-15), g2 = 12(8-20), and g3 23(16-26); p = 0.006), with years of disease evolution being correlated with sIL-6R levels (R = 0.417, p0.001). Simple and Clinical Disease Activity Index (SDAI and CDAI) decreased significantly in the three groups. However, EULAR response criteria and remission achievement at 6m was different in the three groups (p = 0.03 and 0.04, respectively). In all. 17 out of the 18 patients in g1 had a good or moderate response to tocilizumab. Conversely, the percentage of patients with no response to tocilizumab was higher in g3 than in g1 and g2. We also observed different changing patterns of IL-6 and sIL-6R levels among the three groups.RA patients could be easily stratified prior to therapeutic intervention with two molecules related to the pathway blocked by tocilizumab. G1 patients, who had the best response to tocilizumab, had the highest level of IL-6 and the lowest level of sIL-6R. more...

Objectives Extended thymectomy is a treatment option for myasthenia gravis (MG), but the surgical indications are controversial. Pathologic features of the thymus can be used to predict surgical outcomes, but there is no reliable method for evaluating these characteristics preoperatively. The purpose of this study was to determine whether anterior mediastinal tissue volume, as measured via 3-dimensional computed tomography (3DCT) volumetry, correlates with serum anti-acetylcholine receptor antibody (AChRAb) levels in patients undergoing thymectomy for myasthenia gravis. Therefore, we investigated the relationships among anterior mediastinal tissue volume determined by 3DCT volumetry and AChRAb levels. Methods The subjects were 28 patients who underwent extended thymectomy and were enrolled retrospectively. We measured volume of the anterior mediastinum and calculated the volumes of more than −30 Hounsfield units (V −30 ) by using 3DCT volumetry and compared them with perioperative AChRAb levels. The significance of their volumes in MG was examined by comparison with 53 patients without MG. Results V −30 values were related to age and were significantly greater in patients with MG than in patients without MG ( P −30 values were correlated positively with preoperative AChRAb levels (ρ = 0.505, P = .006) and inversely with the post/preoperative AChRAb ratio (ρ = −0.453, P = .018). The histologic nonadipose tissue ratio was correlated with the V −30 /volume of the anterior mediastinum (ρ = 0.700, P Conclusions This method for evaluation of the anterior mediastinal tissue volume and AChRAb production may be helpful in establishing a treatment plan for MG. more...

Recent studies show that the frequencies of circulating follicullar helper T (cTfh) cells are significantly higher in myasthenia gravis (MG) patients compared with healthy controls (HC). And, they are positively correlated with levels of serum anti-acetylcholine receptor antibody (anti-AchR Ab). It is unclear whether cTfh cell subset frequencies are altered and what role they play in MG patients. In order to clarify this, we examined the frequencies of cTfh cell counterparts, their subsets, and circulating plasmablasts in MG patients by flow cytometry. We determined the concentrations of serum anti-AChR Ab by enzyme-linked immunosorbent assay (ELISA). We assayed the function of cTfh cell subsets by flow cytometry and real-time polymerase chain reaction (RT-PCR). We found higher frequencies of cTfh cell counterparts, cTfh-Th17 cells, and plasmablasts in MG patients compared with HC. The frequencies of cTfh cell counterparts and cTfh-Th17 cells were positively correlated with the frequencies of plasmablasts and the concentrations of anti-AChR Ab in MG patients. Functional assays showed that activated cTfh-Th17 cells highly expressed key molecular features of Tfh cells including ICOS, PD-1, and IL-21. Results indicate that, just like cTfh cell counterparts, cTfh-Th17 cells may play a role in the immunopathogenesis and the production of anti-AChR Ab of MG. more...

In this chapter we explain: When immunology tests are most helpful How diagnostic information is gained from measuring: Immunoglobulins and free light chains Anti-nuclear antibody Complement components C3 and C4 Anti-neutrophil cytoplasmic antibody (ANCA) Anti-glomerular basement membrane antibody Anti-phospholipase A2 receptor antibody more...

Drug delivery to the brain is a tremendous problem for the academic society and the industry. One solution with a huge potential is to use endocytic receptors as carriers. Here we describe how endocytic activity and subcellular trafficking of a specific receptor in brain endothelial cells can be characterized in three steps. (1) Labeling, endocytosis, and trafficking of a specific receptor at given time points in a pulse-chase experiment. (2) Fixed antibody labeling and co-staining of subcellular markers for image acquisition. (3) Analysis and quantification of co-localization between the receptor and subcellular markers in ImageJ. more...

KSHV-associated inflammatory cytokine syndrome (KICS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). KICS is associated with high-level, systemic replication of KSHV. This study characterized the clinical and virologic features of a KICS patient over time. Additionally, it compared the cytokine profiles of the KICS case to Kaposi's sarcoma (KS) (n = 11) and non-KS (n = 6) cases. This KICS case presented with elevated levels of KSHV and IL-10, as expected. Surprisingly, this case did not have elevated levels of IL-6 or human immunodeficiency virus 1 (HIV-1). Nevertheless, treatment with anti-IL6 receptor antibody (tocilizumab) reduced KSHV viral load and IL-10. The KSHV genome sequence showed no significant changes over time, except in ORF24. Phylogenetic analysis established this isolate as belonging to KSHV clade A and closely related to other US isolates. These findings suggest IL-10 as potential biomarker and therapy target for KICS. more...

Background Primary Sjogren’s syndrome (pSS) is an idiopathic autoimmune disease whose major clinical manifestations are xerostomia and keratoconjunctive sicca, and is often accompanied with hypergammaglobulinemia. Several lines of evidence suggest that a focal lymphocytic infiltrate of the exocrine glands is responsible for lesion formation, IgG production and subsequent dysfunction of the glands. It is well known that B cell activating factor (BAFF) and its receptor, BR3, are deeply involved in the pathogenesis of pSS, and hence BAFF and BR3 are promising targets to treat the disease. We have reported that the abnormally elevated expression of BR3 in monocytes is associated with overproduction of inflammatory cytokines, such as IL-6, by monocytes of pSS patients. Our in vitro experiments suggest that BAFF-stimulated monocytes contribute to IgG overproduction by pSS B cells. We also found that the population of a specific subset of B cells overexpressing BR3 was abnormally increased in pSS patients and that the proportion of the subset was positively and significantly correlated with serum levels of autoantibodies and total IgG as well as ESSDAI, one of the indicators of disease activity of pSS. Our results collectively suggest that the elevated expression of BR3 in pSS monocytes results in B cell activation and subsequent overproduction of IgG. However, the relationship between the abnormalities of peripheral cells and clinical manifestations of pSS has not been fully understood. Objectives To elucidate possible roles of abnormal monocytes in the development of clinical manifestations of pSS. Methods The expression level of BR3 in peripheral monocytes of patients with pSS (n = 65) and healthy controls (HC: n = 38) was analyzed by FACS. Peripheral B cells were cultured with BAFF-stimulated monocytes in the presence or absence of an anti-IL-6 receptor antibody, and the proportion of CD38highIgDlow cells among CD19+ cells, and IgG production were analyzed by FACS and ELISA, respectively. The serological data and focus scores by lip biopsy of the patients were collected by clinical records. Results FACS analysis revealed that the expression level of BR3 in pSS monocytes was significantly higher than that of HC (p Conclusion Our data strongly suggest that accelerated signal transduction through a BAFF-BR3 axis in monocytes is involved in the pathogenesis of pSS and associates with clinical manifestations of the disease. These results also suggest that BAFF and the BAFF signaling pathways through BR3 are the possible therapeutic targets for pSS. Disclosure of Interests Keiko Yoshimoto: None declared, Katsuya Suzuki: None declared, Yumi Ikeda: None declared, Eriko Takei: None declared, Tsutomu Takeuchi Grant/research support from: Astellas Pharma Inc, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co. Ltd., Novartis Pharma K.K., Grant/research support from: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Grant/research support from: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co.Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., UCB Japan Co. Ltd., Consultant for: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol Myers Squibb, and Nipponkayaku Co. Ltd., Speakers bureau: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Speakers bureau: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma Inc, Diaichi Sankyo Co. Ltd., Eisai Co. Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K. more...

Background: Polymyalgia rheumatica (PMR) is the most common inflammatory disease in the elderly. The 2015 EULAR/ACR recommendations indicate that the management of PMR should be started with glucocorticoids (GCs) and if needed, followed by addition of methotrexate (MTX). The anti-interleukin-6 (IL-6) receptor antibody, tocilizumab (TCZ), has been shown to be effective for PMR. Objectives: To determine the efficacy and safety of TCZ in patients with refractory PMR who were resistant to or intolerant of GCs plus MTX and characterize the clinical profile of patients who need TCZ. Methods: Patients were diagnosed with PMR by the 2012 EULAR/ACR provisional classification criteria and treated according to the 2015 aCR/EULAR recommendations for the management of PMR. TCZ was further added to the patients who were GC plus MTX (GC/MTX)-resistant or -intolerant. The efficacy of treatment was determined by measuring the disease activity with PMR activity score (PMR-AS). We statistically analyzed the differences in clinical indicators between GC-responders, GC/MTX-responders, and GC/MTX-non-responders who need TCZ therapy. Results: Ninety-three patients (53 females and 40 males) were the average of 72.1 ± 9.4 years old, serum CRP 63 ± 42 mg/L, ESR 84 ± 34 mm/hr and blood platelet counts 331 ± 86 ×103/μl, at the first visit, and had been followed up for 25.4±19.6 months. All of them were treated first with prednisolone (PSL) (15.7± 4.3 mg/day). Relapses occurred in 43 patients (46.2%), at the PSL dose of 6.0 ± 5.6 mg/day, after 8.8 ± 6.7 month-GC treatment. GC was increased in 7 patients, and MTX (8.6 ± 2.9 mg/week) was added in 36 patients. Thirteen patients successfully discontinued GC, while 23 patients (24.7%) were resistant to or intolerant of GC/MTX. Ten of 23 patients agreed with TCZ therapy. Before TCZ addition, they were treated with PSL of 6.0 ± 2.2 mg/day plus MTX of 6.0 ± 3.8 mg/week, and serum CRP 9.7 ± 9 mg/L, blood platelet counts 271 ± 32 ×103/μl and PMR-AS 15.5 ±13.5. After 7.3 ± 4.2 month-TCZ treatment, PSL and MTX were reduced to 1.3 ± 1.6 mg/day and 2.2 ± 3.0 mg/week, and CRP, blood platelet counts and PMR-AS decreased to Conclusion: TCZ may provide a therapeutic option for patients with refractory PMR who were resistant to or intolerant of GC/MTX. Our retrospective results suggest that patients with severe PMR, who show thrombocytosis and need high dose GC for initial therapy, may be considered for early induction of TCZ. Disclosure of interests: None declared more...

Background Aortitis can be idiopathic or associated with other conditions. It is frequently refractory to conventional immunosuppressive therapy. Tocilizumab (TCZ), an anti-IL-6 receptor antibody seems to be effective and safe. Objectives Our aim was to assess the efficacy and safety of TCZ at short and long follow-up in a series of patients with Aortitis. Methods Retrospective, multicenter study of 79 patients diagnosed of inflammatory aortitis based on imaging techniques (PET/CT, CT angiography and/or MR angiography). Results We study 79 patients (61 w/ 18 m). 59 (74.7%) cases were Aortitis secondary to Giant Cell Arteritis (GCA), while 20 (25.3%) were idiopathic. The mean age was 71±8.5 years vs 64.2±7.1 years, respectively (p=0.001). At time of disease diagnosis more than a half of patients (59.5%) presented as main symptom polymyalgia rheumatica (PMR). Aortitis was diagnosed with PET/CT (71 patients), angioRMN (12 patients) and angioCT (8 patients). Prior to TCZ treatment, 61 (77.2%) patients had received conventional immunosuppressive drugs, 59 (74.7%) of them received MTX. After 24 months of treatment with TCZ, more than 75% of patients reached a prolonged remission in both groups (p=0.527), with only 4% of relapses after the same follow-up period (p=1.000). 40 (50.6%) patients had a control image technique (PET/CT) throughout follow up. 4 (3 secondary to GCA and 1 idiopathic) patients reached a complete improvement in uptake after one year of treatment. Conclusion Our results show that idiopathic aortitis occurs in younger patients compared with aortitis secondary to GCA. TCZ proved to be effective in both pathologies, allowing clinical and analytical improvement, as well as a reduction of corticoid dose, without increasing the risk of relapse. However, the improvement in imaging techniques seems to be slower. Reference [1] Loricera J, Blanco R, Castaneda S, Humbria A, Ortego-Centeno N, Narvaez J, et al. Tocilizumab in refractory aortitis: study on 16 patients and literature review. Clin Exp Rheumatol. 2014; 32:79-89. Disclosure of Interests Monica Calderon-Goercke: None declared, J. Loricera: None declared, D. Prieto-Pena: None declared, Vicente Aldasoro: None declared, Santos Castaneda Consultant for: Amgen, BMS, Pfizer, Lilly, MSD, Roche, Sanofi, UCB, Ignacio Villa-Blanco: None declared, Alicia Humbria: None declared, Clara Moriano: None declared, Susana Romero-Yuste: None declared, J. Narvaez Consultant for: Bristol-Myers Squibb, Catalina Gomez-Arango: None declared, Eva Perez-Pampin: None declared, Rafael Melero: None declared, Marcelino Revenga: None declared, Noelia Alvarez-Rivas: None declared, Francisca Sivera: None declared, Maria Alvarez del Buergo: None declared, Luisa Marena Rojas: None declared, Eva Galindez: None declared, Beatriz Arca: None declared, Roser Solans-Laque: None declared, Carlos Vazquez: None declared, Pau Lluch: None declared, Eva Salgado-Perez: None declared, Cristina Luna-Gomez: None declared, Francisco J. Toyos Saenz de Miera: None declared, Nagore Fernandez-Llanio: None declared, Antonio Garcia: None declared, Carmen Larena: None declared, Natalia Palmou-Fontana: None declared, Vanesa Calvo-Rio: None declared, Carmen Gonzalez-Vela: None declared, Alfonso Corrales: None declared, Maria Varela-Garcia: None declared, Elena Aurrecoechea: None declared, Raquel Dos-Santos: None declared, Jose Luis Martin-Varillas: None declared, Sabela Fernandez: None declared, J. Luis Hernandez: None declared, Miguel A Gonzalez-Gay Grant/research support from: Prof. MA Gonzalez-Gay received grants/research supports from Abbvie, MSD, Jansen and Roche., Speakers bureau: Consultation fees/participation in company sponsored speaker’s bureau from Pfizer, Lilly, Sobi, Celgene, Novartis, Roche and Sanofi., Ricardo Blanco Grant/research support from: Abbvie, MSD, and Roche, Consultant for: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen more...

Background: The anti–interleukin-6 receptor antibody tocilizumab is approved for subcutaneous injection using a prefilled syringe (PFS). We report results from a bioequivalence study in healthy subjects and a user-handling study in patients with rheumatoid arthritis (RA) using an autoinjector (AI) for tocilizumab. Methods: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI. Results: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns. Conclusions: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study. Clinical Trial Registration: NCT02678988, NCT02682823 more...

The IL-6 receptor antibody tocilizumab abolished the ability of exercise to reduce visceral fat and cholesterol levels in obese individuals.

Objective TSH receptor antibodies (TRAb) are responsible for autoimmune hyperthyroid disease (Graves' disease; GD) with TRAb levels tending to decrease following treatment. Measurement of TRAb activity during follow-up could prove valuable to better understand treatment effectiveness. Study design TRAb concentration and stimulating (TSAb) and blocking (TSBAb) activity of patient serum were assessed following different treatment modalities and follow-up length. Methods Sixty-six subjects were recruited following treatment with carbimazole (n = 26), radioiodine (n = 27) or surgery (n = 13). TRAb, TPOAb, TgAb and GADAb were measured at a follow-up visit as well as bioassays of TSAb and TSBAb activity. Results Forty-five per cent of all patients remained TRAb-positive for more than one year and 23% for more than 5 years after diagnosis, irrespective of treatment method. Overall, TRAb concentration fell from a median (IQR) of 6.25 (3.9-12.7) to 0.65 (0.38-3.2) U/L. Surgery conferred the largest fall in TRAb concentration from 11.4 (6.7-29) to 0.58 (0.4-1.4) U/L. Seventy per cent of TRAb-positive patients were positive for TSAb, and one patient (3%) was positive for TSBAb. TRAb and TSAb correlated well (r = 0.83). In addition, 38/66 patients were TgAb-positive, 47/66 were TPOAb-positive and 6/66 were GADAb-positive at follow-up. Conclusions TRAb levels generally decreased after treatment but persisted for over 5 years in some patients. TRAb activity was predominantly stimulatory, with only one patient demonstrating TSBAb. A large proportion of patients were TgAb/TPOAb-positive at follow-up. All treatment modalities reduced TRAb concentrations; however, surgery was most effective. more...

We aimed to evaluate the impact of induction on outcomes in low-immunological risk kidney transplant recipients (KTRs) using a mate-kidney model. Using OPTN/UNOS database, we identified three groups of low-immunological risk KTRs (first transplant, panel reactive antibody more...

OBJECTIVE Intravenous methylprednisolone (IVMP) is recommended as the first-line treatment for moderate-to-severe and active thyroid-associated ophthalmopathy (TAO). This study aimed to identify potential predictors and establish a multivariable prediction model for the efficacy of IVMP therapy. DESIGN A single-centre retrospective study. PATIENTS A total of 302 consecutive patients diagnosed with moderate-to-severe and active TAO who underwent the full course of IVMP therapy were included. METHODS Participants were sequentially divided into the training set (n = 200) and the validation set (n = 102). Multivariate logistic regression analysis was used to identify the independent predictors and establish the predictive model. RESULTS In addition to the pretreatment clinical activity score (OR = 3.506, P more...

Aptamers represent the novel class of oligonucleotides holding multiple applications in the area of biomedicine. The advancements introduced with the Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach further eased the scope of producing modified aptamers within a short span yet retaining the properties of stability and applicability. In the recent times, aptamers were identified to have the potential for penetrating into the deep human crevices and thus can be utilized in addressing the issues of complex neurological disorders. Considering the specificity and stability enhancement by chemical modifications, aptamer-based nanotechnologies may have great potential for future therapeutics and diagnostics (theranostics). The research community has already witnessed success with the approval of macugen (an anti-vascular endothelial growth factor aptamer) for treating degenerating eye disease, and hopefully those that are in the clinical trials will soon be translated for human application. Herein, we have summarized the aptamer chemistry, aptamer-nanoconjugates and their applications against neurological diseases. more...