Onset Of Relapse Research Articles

Progress in progressive MS

Remarkably, progressive MS has stood the test of time and is still with us. This is despite longstanding difficulties with the diagnosis of progressive MS, the onset of progressive MS in patients with initial relapse onset disease, the translation of conceptual progressive MS to the individual patient and importantly a secure understanding of the processes underlying progression. Nevertheless, despite these difficulties there is appreciable progress in all these areas which will be highlighted to illustrate the changes that are under way. Firstly, a diagnosis of primary progressive MS depends on the absence of a recognised relapse. Fortunately, we now have one highly effective anti-inflammatory medication approved for primary progressive MS. This, in certain circumstances, negates the requirement to delay using anti-inflammatory medication until a relapse or the MRI equivalent occurs. Secondly, many cases of secondary progressive MS have identifiable inflammation and anti-inflammatory medication can improve disability as well as protect relatively spared areas of the CNS such as pathways to the upper limbs and cognition. As a consequence of these changes there is evolving evidence that the effects of secondary progressive MS can be curtailed, if not prevented, by the early use of effective anti-inflammatory medication. Thirdly, there is increasing evidence that the use of progressive worsening of the EDSS in progressive MS treatment trials was likely responsible for the confounding negative outcomes. There is now increasing realisation that advancing lower limb long tract signs more realistically represents degeneration consequent upon past cumulative inflammatory injury at least in part. Fourthly, researchers are now dissecting identifiable pathways that activate the innate immune system and searching to repurpose drugs to modify such activation. The imminent availability of disease activity sensitive fluid biomarkers combined with advances in MRI use in enriched specific patient populations presents the possibility of both positive proof of concept trials to understand the pathogenesis of progression and of therapies targeted to identified pathogenesis rather than to disease phenotypes.

Plasma proteome in multiple sclerosis disease progression.

BackgroundThe pathophysiology of multiple sclerosis disease progression remains undetermined. The aim of this study was to identify differences in plasma proteome during different stages of MS disease progression.MethodsWe used a multiplex aptamer proteomics platform (Somalogic) for sensitive detection of 1129 proteins in plasma. MS patients were selected and categorized based on baseline and a 4‐year follow‐up EDSS (delta EDSS) scores; relapse‐onset (RO) slow progression (n = 31), RO with rapid progression (n = 29), primary progressive (n = 30), and healthy controls (n = 20). The relation of baseline plasma protein levels with delta EDSS and different MRI progression parameters were assessed using linear regression models.ResultsRegression analyses of plasma proteins with delta EDSS showed six significant associations. Strong associations were found for the proteins LGLAS8 (P = 7.64 × 10−5, q = 0.06), CCL3 (P = 0.0001, q = 0.06), and RGMA (P = 0.0005, q = 0.09). In addition, associations of plasma proteins were found with percentage brain volume for C3 (P = 2,08 × 10−9, q = 1,70 × 10−6), FGF9 (P = 3,42 × 10−9, q = 1,70 × 10−6), and EHMT2 (P = 0.0007, q = 0.01). Most of the significant markers were associated with cell‐cell and cell‐extracellular matrix adhesion, immune system communication, immune system activation, and complement pathways.ConclusionsOur results revealed eight novel biomarkers related to clinical and radiological progression in MS. These results indicate that changes in immune system, complement pathway and ECM remodeling proteins contribute to MS progression and may therefore be further explored for use in prognosis of MS.

The effect of lupus disease on the pregnant women and embryos: a retrospective study from 2010 to 2014.

Pregnancy in women with systemic lupus erythematosus (SLE) is one of the challenges of recent studies. Women should prevent the onset of relapses with medications before and after pregnancy, and on the other hand, the effect of these medicines considers the health and development of the fetus. In this retrospective study, the effects of anti-phospholipid syndrome and the use of common drugs such as methotrexate, cyclosporine, and azathioprine and their side effects on maternal health and ultimately the development of the fetus have been investigated. This study is a descriptive and retrospective epidemiologic study that was conducted in 2016 to investigate maternal and fetal complications in SLE patients. We prepared forms of data recording, including age, occupation, and other important information and then analyzed them in SPSS version 22. The results showed that the presence of anti-phospholipid syndrome in pregnant women can lead to abnormalities such as preterm, IUGR, abortion, and fetal death (P value 0.0001). It also leads to complications such as nephritis, arthritis, and preeclampsia in the mother (P value 0.003). This study suggests that methotrexate and cyclosporine medications could cause fetal developmental disorders. The P value of cyclosporine was 0.0001 and the P value of methotrexate was 0.001. Anti-phospholipid syndrome in women with SLE who intend to become pregnant can disrupt the development of the embryo. The consumption of methotrexate and cyclosporine medications before and during the pregnancy can have irreparable effects on fetal growth. Key Points • Anti-phospholipid syndrome can disrupt the development of the embryo in women with SLE who intend to become pregnant. • Methotrexate and cyclosporine consumption before and during pregnancy can affect fetal growth. • 7 to 33% of patients whose disease had been suppressed and controlled 6months before pregnancy seams to relapse during the pregnancy. • Taking medications to control the disease during pregnancy plays an important role in the progression of pregnancy and fetus health.

Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer

BackgroundThe oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplified breast cancer patients for two decades. However, the lack of response and the rapid onset of relapse in many patients now question the assumption that the ERBB2/ERBB3 heterodimer is the sole relevant effector target of these therapies.MethodsThrough a systematic protein-protein interaction screen, we have identified and validated alternative RTKs that interact with ERBB2. Using quantitative readouts of signalling pathway activation and cell proliferation, we have examined their influence upon the mechanism of trastuzumab- and pertuzumab-mediated inhibition of cell growth in ERBB2-amplified breast cancer cell lines and a patient-derived xenograft model.ResultsWe now demonstrate that inactivation of ERBB3/PI3K by these therapeutic antibodies is insufficient to inhibit the growth of ERBB2-amplified breast cancer cells. Instead, we show extensive promiscuity between ERBB2 and an array of RTKs from outside of the EGFR family. Paradoxically, pertuzumab also acts as an artificial ligand to promote ERBB2 activation and ERK signalling, through allosteric activation by a subset of these non-canonical RTKs. However, this unexpected activation mechanism also increases the sensitivity of the receptor network to the ERBB2 kinase inhibitor lapatinib, which in combination with pertuzumab, displays a synergistic effect in single-agent resistant cell lines and PDX models.ConclusionsThe interaction of ERBB2 with a number of non-canonical RTKs activates a compensatory signalling response following treatment with pertuzumab, although a counter-intuitive combination of ERBB2 antibody therapy and a kinase inhibitor can overcome this innate therapeutic resistance.

Cytomegalovirus-specific CD8+ T-cells are associated with a reduced incidence of early relapse after allogeneic stem cell transplantation.

Leukemia relapse is the main cause for mortality after allogeneic stem cell transplantation (allo-SCT). Donor-derived allo-immune responses eliminate the residual host hematopoiesis and protect against relapse. Cytomegalovirus (CMV) reactivation (CMV-R) after allo-SCT may trigger anti-leukemic effects. The impact of CMV-specific CD8+ T-cells (CMV-CTLs) on the outcome after allo-SCT is currently unknown. Here, we studied the relationship between CMV-CTLs, overall T-cell reconstitution and relapse incidence in 103 patients with acute leukemia (n = 91) or myelodysplastic syndrome (n = 12) following CMV-seropositive recipient/donor (R+/D+) allo-SCT. Patients were subdivided based on the presence or absence of CMV-CTLs at 3 months after allo-SCT. Presence of CMV-CTLs was associated with preceding CMV-R and a fast T-cell reconstitution. Univariate analysis showed a significantly lower 1-, 2- and 5-year cumulative incidence of relapse (CIR) in patients with CMV-CTLs compared to those without CMV-CTLs. Multivariable regression analysis of the outcome performed with other relevant parameters chosen from univariate analysis revealed that presence of CMV-CTLs and chronic graft-versus-host disease (cGvHD) were the only independent factors associated with a low CIR. Onset of relapse was significantly later in patients with CMV-CTLs (median 489 days) than in in those without (median 152 days, p = 0.041) during a five-year follow-up. Presence of CMV-CTLs was associated with a lower incidence of early relapses (1 and 2-years), while cGvHD lead to a lower incidence of late relapses (2 to 5-years). In conclusion, our data show that CMV-CTLs indicate a functional immune-reconstitution protective against early relapse.

SFX-01 reduces residual disability after experimental autoimmune encephalomyelitis

BackgroundNuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a master transcriptional regulator of the protective cellular response to oxidative stress. Sulforaphane is a Nrf2 activator but is unstable at ambient temperature. SFX-01 is a novel composition comprised of synthetic sulforaphane stabilised within the pocket of an α-cyclodextrin complex. Here we tested the efficacy of SFX-01 in murine relapsing experimental autoimmune encephalomyelitis (EAE), a model of relapsing-remitting MS (RRMS). MethodsRelapsing EAE was induced in female SJL mice using immunization against PLP139-151. In the therapeutic experiment, the aim was to model initiation of treatment after diagnosis in RRMS, so treatment was started at day 19, one day prior to the expected relapse onset. In the prophylactic experiment, mice were treated from the time of immunization and followed for three weeks. ResultsSFX-01 reduced residual disability in both experiments. Most of this effect was mediated by a decrease in maximum severity of relapses and improved recovery during follow-up. Histological examination of the spinal cord was consistent with the clinical findings, with improvement in demyelination and the number of apoptotic cells, but not inflammatory cell infiltration, compared to the vehicle group. ConclusionsSFX-01 is efficacious in EAE. In first-in-man and phase II clinical trials for other indications, SFX-01 was found to be well-tolerated. A trial comparing BG-12 and SFX-01 would address whether SFX-01 can offer RRMS patients a better option with respect to efficacy and tolerability.

Factors predicting local relapse and survival in patients treated with surgery for breast cancer

Assessment of local relapse in patients treated with surgery for breast cancer. This observational study included 673 patients treated with surgery for breast cancer between 2005 and 2010, who were monitored for a 7-year minimum follow-up period. The study was concluded on 2017 and yielded a total of 31 cases of local relapse. 4.6% of patients presented local relapse, most of them during the first 3 years of follow-up; 45% of patients with local relapse subsequently presented the disease at distant points. The association between the occurrence of local relapse and later onset of the disease at distant points was significant. The Kaplan-Meier survival analysis revealed that negative results for the presence of progesterone receptors, the use of neoadjuvant chemotherapy and the presence of the disease at distant points were factors that significantly influenced patient survival. Almost half of the patients suffering relapse subsequently present the disease at distant points. Certain factors increase the aggressiveness of the disease, predict higher risk of relapse and determine its prognosis.

Identification of Chemotherapy-Induced Leukemic-Regenerating Cells Reveals a Transient Vulnerability of Human AML Recurrence

Despite successful remission induction, recurrence of acute myeloid leukemia (AML) remains a clinical obstacle thought to be caused by the retention of dormant leukemic stem cells (LSCs). Using chemotherapy-treated AML xenografts and patient samples, we have modeled patient remission and relapse kinetics to reveal that LSCs are effectively depleted via cell-cycle recruitment, leaving the origins of relapse unclear. Post-chemotherapy, invivo characterization at the onset of disease relapse revealed a unique molecular state of leukemic-regenerating cells (LRCs) responsible for disease re-growth. LRCs are transient, can only be detected invivo, and are molecularly distinct from therapy-naive LSCs. We demonstrate that LRC features can be used as markers of relapse and are therapeutically targetable to prevent disease recurrence.

Balance Changes in Patients With Relapsing-Remitting Multiple Sclerosis: A Pilot Study Comparing the Dynamics of the Relapse and Remitting Phases.

Aims: To compare balance changes over time during the relapse phase of relapsing-remitting multiple sclerosis (RRMS) with balance control during the remitting phase.Methods: Balance control during stance and gait tasks of 24 remitting-phase patients (mean age 43.7 ± 10.5, 15 women, mean EDSS at baseline 2.45 ± 1.01) was examined every 3 months over 9 months and compared to that of nine relapsing patients (age 42.0 ± 12.7, all women, mean EDSS at relapse onset 3.11 ± 0.96) examined at relapse onset and 3 months later. Balance was also compared to that of 40 healthy controls (HCs) (age 39.7 ± 12.6, 25 women). Balance control was measured as lower-trunk sway angles with body-worn gyroscopes. Expanded Disability Status Scale scores (EDSS) were used to monitor, clinically, disease progression.Results: Remitting-phase patients showed more unstable stance balance control than HCs (p < 0.04) with no worsening over the observation period of 9 months. Gait balance control was normal (p > 0.06). Relapsing patients had stance balance control significantly worse at onset compared to remitting-phase patients and HCs (p < 0.04). Gait tasks showed a significant decrease of gait speed and trunk sway in relapsing patients (p = 0.018) compatible with having increased gait instability at normal speeds. Improvement to levels of remitting patients generally took longer than 3 months. Balance and EDSS scores were correlated for remitting but not for relapse patients.Conclusions: Balance in remitting RRMS patients does not change significantly over 9 months and correlated well with EDSS scores. Our results indicate that balance control is a useful measure to assess recovery after a relapse, particularly in patients with unchanged EDSS scores. Based on our results, balance could be considered as additional measurement to assess recovery after a relapse, particularly in patients with unchanged EDSS.

Functional Connectivity Alterations Reveal Complex Mechanisms Based on Clinical and Radiological Status in Mild Relapsing Remitting Multiple Sclerosis.

Resting state functional MRI (rs-fMRI) has provided important insights into functional reorganization in subjects with Multiple Sclerosis (MS) at different stage of disease. In this cross-sectional study we first assessed, by means of rs-fMRI, the impact of overall T2 lesion load (T2LL) and MS severity score (MSSS) on resting state networks (RSNs) in 62 relapsing remitting MS (RRMS) patients with mild disability (MSSS < 3). Independent Component Analysis (ICA) followed by dual regression analysis confirmed functional connectivity (FC) alterations of many RSNs in RRMS subjects compared to healthy controls. The anterior default mode network (DMNa) and the superior precuneus network (PNsup) showed the largest areas of decreased FC, while the sensory motor networks area M1 (SMNm1) and the medial visual network (MVN) showed the largest areas of increased FC. In order to better understand the nature of these alterations as well as the mechanisms of functional alterations in MS we proposed a method, based on linear regression, that takes into account FC changes and their correlation with T2LL and MSSS. Depending on the sign of the correlation between FC and T2LL, and furthermore the sign of the correlation with MSSS, we suggested the following possible underlying mechanisms to interpret altered FC: (1) FC reduction driven by MS lesions, (2) “true” functional compensatory mechanism, (3a) functional compensation attempt, (3b) “false” functional compensation, (4a) neurodegeneration, (4b) pre-symptomatic condition (damage precedes MS clinical manifestation). Our data shows areas satisfying 4 of these 6 conditions (i.e., 1,2,3b,4b), supporting the suggestion that increased FC has a complex nature that may exceed the simplistic assumption of an underlying compensatory mechanism attempting to limit the brain damage caused by MS progression. Exploring differences between RRMS subjects with short disease duration (MSshort) and RRMS with similar disability but longer disease duration (MSlong), we found that MSshort and MSlong were characterized by clearly distinct pattern of FC, involving predominantly sensory and cognitive networks respectively. Overall, these results suggest that the analysis of FC alterations in multiple large-scale networks in relation to radiological (T2LL) and clinical (MSSS, disease duration) status may provide new insights into the pathophysiology of relapse onset MS evolution.

Successful Treatment of Focal Segmental Glomerulosclerosis Recurrence in a Second Kidney Transplant Patient: A Case Report

BackgroundRecurrence of focal segmental glomerulosclerosis (FSGS) in renal allograft recipients after first transplant occurs in the second graft in virtually all patients. There is little evidence regarding optimal treatment. Case presentationA 55-year-old man with primary FSGS and disease recurrence in both the first and the second kidney grafts is presented. In 1999, the patient developed FSGS 3 years after transplant, which was treated with plasmapheresis and cyclophosphamide. Hemodialysis was started at 8 years from the onset of relapse. In February 2014, the patient received a second kidney transplant, and after 2 weeks laboratory analysis showed nephrotic proteinuria (5.9 g/d) with increased serum creatinine. Biopsy results revealed recurrence of FSGS. At that time, he was treated with steroids and plasmapheresis with partial efficacy, achieving a serum creatinine level of 1.1 mg/dL with decreased proteinuria (1 g/d). After 4 months, creatinine worsened (1.6 mg/dL) with new evidence of proteinuria. Second biopsy results showed evidence of FSGS progression. The patient then received plasmapheresis and 2 doses of rituximab. Follow-up was characterized by progressive remission up to complete resolution. The patient is currently free from relapses after 3 years with good renal function and almost no proteinuria. ConclusionsMore evidence and prospective studies are needed to better understand the role of rituximab in FSGS in order to obtain an optimized therapeutic protocol for recurrence of FSGS in renal transplant recipients.

Relapse After Antipsychotic Discontinuation in Schizophrenia as a Withdrawal Phenomenon vs Illness Recurrence

It has been proposed that relapse rates after antipsychotic discontinuation may be artificially inflated and that some of these symptom recurrences may be due to rebound or withdrawal phenomena rather than due to illness recurrence. Post hoc analysis of data from a relapse-prevention study (conducted from March 2005 to February 2007) of paliperidone palmitate once-monthly (PP1M) versus placebo was conducted to compare the nature of operationally defined relapse events in schizophrenia patients (diagnosed by DSM-IV criteria) experiencing relapses after randomization to placebo (n = 97) with those in patients receiving maintenance PP1M treatment (n = 36). These 2 groups were compared for onset and severity of recurrence symptoms, symptom profiles at relapse, and postrelapse treatment response. Psychological and physiological signs of discontinuation and signs of antipsychotic tolerance, dyskinesia, and prolactin elevation that might indicate dopamine receptor supersensitivity were compared. Both groups were similar in terms of relapse symptom profiles, onset and severity of relapse symptoms, and postrelapse treatment response. The Positive and Negative Syndrome Scale total score (mean ± SD) for placebo versus maintenance treatment group at baseline was 54.5 ± 11.74 vs 54.1 ± 11.64 and at relapse was 75.6 ± 16.79 vs 75.2 ± 17.23 (P = .9). No elevated blood pressure or heart rate, dyskinesia, antipsychotic tolerance, or elevated prolactin in the patients relapsing after antipsychotic discontinuation was noted. Findings suggest that relapses after treatment discontinuation reflect recurrence of the underlying illness and may be consistent with a hypothesis of direct relationship between dopamine and psychosis. No evidence was obtained for withdrawal-related phenomena contributing to the high relapse rates after treatment discontinuation. ClinicalTrials.gov identifier: NCT00111189.

Association of Pre-Disease Body Mass Index With Multiple Sclerosis Prognosis.

Both high body mass index (BMI) and smoking tobacco are known risk factors for developing multiple sclerosis (MS). However, it is unclear whether BMI, like smoking, is a risk factor for the secondary progressive (SP) course. We, therefore, sought to determine if high/low BMI at age 20 is associated to risk of SP development, in the context of smoking status. Using data from MS patients with BMI and smoking information available, we examined relapsing onset patients with MS onset after 20 years of age. Cox regressions were conducted on smokers and non-smokers, with BMI as the main exposure. In total, 5,598 relapsing onset MS patients were included. The models demonstrated that BMI > 30 was associated to increased risk of SPMS in smokers (hazard ratio 1.50, p = 0.036). This association of obesity at age 20 with increased risk of SP was not observed in non-smokers (hazard rate 0.97, p = 0.900). Since the risk is confined to smokers, the interaction observed may give insight to disease driving mechanisms.

MINIMAL RESIDUAL DISEASE ASSESMENT IN PATIENTS WITH ACUTE MYELOID LEUKEMIA BY MULTICOLOUR FLOW CYTOMETRY (LITERATURE REVIEW)

Patients with acute myeloid leukemia (AML) have a high risk of relapse. Determination of the presence of residual tumor cells during the remission of AML allows predicting the onset of relapse. Slow decrease of blast cells after induction courses is associated with a high probability of relapse. There are two most sensitive methods for determining minimal residual disease (MRD): molecular (polymerase chain reaction – PCR, droplet digital PCR, next generation sequencing – NGS) and immunophenotypic (multicolor flow cytometry – MFC). Both methods have advantages and disadvantages. The molecular diagnostic method is more sensitive, but it takes more time to get the result (from several days). Measurement of MRD by PCR is applicable in 40–50 % of AML patients, and by MFC – in 90 % of patients. The MFC method is based on the identification of antigens combination that is characteristic of tumor cells and is not found on normal hematopoietic cells. There are several drawbacks of the MFC method: the change of tumor clone immunophenotype during treatment, the inadequate difference in the antigen profiles of tumor cells and normal cells, difficulties in evaluating the MRD status in low cellularity bone marrow or blood sample. In AML patients the effect of MRD, measured by the MFC method, on long-term treatment outcomes was well-demonstrated. Evaluation of early MRD status shows tumor chemosensitivity and therapy efficacy. Despite the different approaches in MRD detection, thresholds and the combination of monoclonal antibodies, the lack of standardization, “positive” MRD values in early or later stages of therapy worsen the disease-free (DFS) and overall survival (OS) in AML patients. So far, the principles of MRD-directed therapy have not been developed, but protocols exist with the use of targeted drugs in combination with standard chemotherapy that help to reduce the MRD level. It is proved that the intensification of treatment does not affect the quantitative value of MRD and the long-term results of therapy. New prospective studies are needed to search for universal MRD markers, to create a standardized panel of monoclonal antibodies and to develop a specific therapy strategy in accordance with the MRD values.

Ambient Air Pollution and Occurrence of Multiple Sclerosis Relapses

Background/Aim: Triggers of multiple sclerosis (MS) relapses are essentially unknown. Relapses' incidence varies across seasons, suggesting a possible role of season-dependent factors such as meteorological variables and ambient air pollution. Relatively few studies have investigated this hypothesis, but the role of ambient air pollution is of growing interest; a recent study from our group observed an increased risk of relapses with ambient PM10 exposures until 3 days before the relapse onset (cold season). Methods: We conducted a time-stratified case-crossover design to further explore separately the short-term associations between other pollutants (e.g., NO2, Benzene (C6H6), O3, and CO) and the odds of MS relapses occurrence. Our study population consists of 536 relapsing MS patients living in Strasbourg area (France) who experienced 2,052 relapses (2000-2009). Control days are chosen to be ±35 days relative to the case (relapse) day. We performed a conditional logistic regression coupled with a distributed-lag model (considering lags 0 to 3) using the "dlnm" R package, stratified by season (hot and cold), and adjusted on all lagged meteorological variables (daily maximum temperature, maximum relative humidity and maximum atmospheric pressure), lagged pollen count, lagged influenza-like epidemics, and holidays. Results: An interquartile range increase in NO2 (lags 1 to 3 cumulated) was associated with MS relapses incidence (ORNO2=1.28 [95%CI: 1.05-1.55]) during cold months (i.e., October to March). C6H6 and CO were not significantly related to MS relapse incidence (ORC6H6=1.13 [95%CI: 0.95-1.35] and ORco=1.09 [95%CI: 0.89-1.34], respectively). We also observed non-significant association between O3 during hot months and MS relapse incidence (ORO3=1.12 [95%CI: 0.88-1.44]). Conclusions: We found a significant association between NO2 and the occurrence of MS relapses using a case-crossover design, relevant to studies with rare event outcomes. Strengths of our study include a precise exposure spatio-temporal model and a clinically-diagnosed outcome from a fairly exhaustive MS registry.

Tryptophan immunoadsorption during pregnancy and breastfeeding in patients with acute relapse of multiple sclerosis and neuromyelitis optica

Background:Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce.Methods:In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON).Results:A total of 24 patients were analyzed, 23 with relapsing–remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7–10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments.Conclusions:Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.

Paroxysmal and unusual symptoms as first clinical manifestation of multiple sclerosis do not indicate benign prognosis-The PaSiMS II study.

BackgroundParoxysmal (PS) and unusual symptoms (US) account for approximately 1.6% of initial manifestations of multiple sclerosis (MS) and have comparable conversion rates to clinically definite MS (CDMS) as classical bout onset symptoms (CS). However, long-term prognosis and clinical outcome of patients experiencing PS or US as first clinical manifestation are unclear.MethodsClinical, MRI and cerebrospinal fluid data were obtained retrospectively and patients presenting with PS or US were compared to patients with CS presentation.ResultsIn a cohort of 532 relapsing onset MS patients followed for a mean period of 11.4 years (SD 3.6), 10 (1.9%) patients initially presented with PS/US. PS/US patients received disease modifying treatment (DMT) in a significantly smaller proportion immediately after the first clinical symptom (30% vs. 61.7%; p = 0.021) and during the observation period (60% vs. 83.5%; p = 0.033). In multivariate models correcting for sex, age at initial symptoms, complete remission of initial symptoms, total number of T2 and contrast-enhancing lesions, presence of oligoclonal bands and DMT exposure, PS/US were not associated with lower annualized relapse rate or lower EDSS over time.ConclusionIn addition to a similar conversion rate to CDMS, patients presenting with PS/US at disease onset display very similar relapse and disability rates as patients with CS onset. Consequently, initial presentation with PS/US does not indicate benign or atypical MS, but requires DMT initiation based on the same criteria as in CS patients.

A serum CNS-specific protein fingerprint predictive of clinical relapses and disease development of multiple sclerosis

Abstract There is a critical need in MS to develop biomarkers to improve early diagnosis, predict imminent disease relapses, and optimize treatment responses. In MS, central nervous system (CNS) inflammation results in damage to neuronal tissues and disruption of blood-brain barrier integrity, and ultimately to leakage of CNS-specific proteins (CSPs) into serum. Therefore, altered serum levels of CSPs could be promising biomarkers of MS. Based on our previous discovery of CSP expression waves in brain tissue of mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model for human MS, we investigated a subset of CSPs which have human-homologs in longitudinal serum specimens from individual mice in this model. Herein, we establish a pre-onset serum CSP expression wave that enabled prediction of clinical onset of EAE and stratification of subjects into diseased versus healthy. Importantly, we demonstrate that the pre-onset serum CSP wave was not affected by adjuvants and microbial infection, thereby has high sensitivity and specificity for a neuroinflammatory disease. Moreover, we identify differences in serum protein expression between active and passive immunization of EAE revealing hitherto not appreciated differences for disease induction mechanisms. The results provide proof of concept for the development serum CSP waves as biomarkers of MS, specifically for early detection and prediction of the onset of clinical relapse.

Air pollution by particulate matter PM10 may trigger multiple sclerosis relapses

BackgroundSeasonal variation of relapses in multiple sclerosis (MS) suggests that season-dependent factors, such as ambient air pollution, may trigger them. However, only few studies have considered possible role of air pollutants as relapse's risk factor. ObjectiveWe investigated the effect of particulate matter of aerodynamic diameter smaller than 10µm (PM10) on MS relapses. MethodsIn total, 536 relapsing MS patients from Strasbourg city (France) were included, accounting for 2052 relapses over 2000–2009 period. A case-crossover design was used with cases defined as the days of relapse and controls being selected in the same patient at plus and minus 35 days. Different lags from 0 to 30 days were considered. Conditional logistic regressions, adjusted on meteorological parameters, school and public holidays, were used and exposure was considered first as a quantitative variable and second, as a binary variable. ResultsThe natural logarithm of the average PM10 concentration lagged from 1 to 3 days before relapse onset was significantly associated with relapse risk (OR =1.40 [95% confidence interval 1.08–1.81]) in cold season. Consistent results were observed when considering PM10 as a binary variable, even if not significant. ConclusionWith an appropriate study design and robust ascertainment of neurological events and exposure, the present study highlights the effect of PM10 on the risk of relapse in MS patients, probably through oxidative stress mechanisms.

Major infections in children with nephrotic syndrome

Background: Infections remain an important cause of mortality and morbidity in children with nephrotic syndrome. It triggers the onset of disease or relapses and may also be responsible for a poor response to steroid therapy. Understanding the type and severity of infections is important in the appropriate management of these children. This study was conducted to determine the frequency and type of major infections in children with nephrotic syndrome.Methods: A longitudinal descriptive study was conducted in a tertiary center, in children between 1 and 12 years with nephrotic syndrome satisfying the International Study of kidney disease in children (ISKDC) criteria, from March 2013 to September 2014. Major infections were defined as infections affecting deep organs and tissues which warrant hospitalization. Results: A total of 246 children with nephrotic syndrome were enrolled, of whom 46 children developed 48(19.6%) episodes of major infections. Thirteen (27%) major infections occurred in the initial episode and 35(73%) in relapse cases. Pneumonia (41.7%) was the commonest infection, followed by urinary tract infection (25%), septicemia (16.7%), spontaneous bacterial peritonitis (8.3%), cellulitis (4.2%), perinephric abscess (2.1%) and pulmonary tuberculosis (2.1%). Two children had multiple infections. Methicillin resistant staphylococcus aureus was the causative organism in 5 children with septicemia. A 24% of bacterial isolates were multidrug resistant.Conclusions: Major infections remain an important complication of nephrotic syndrome in children, especially during relapses. Drug resistant organisms should be considered while treating major infections in these children.