Major Relapse Research Articles

Risk of death, major adverse cardiac events and relapse in patients with bullous pemphigoid treated with systemic or topical corticosteroids.

According to current guidelines, systemic or topical corticosteroids are both recommended as first-line treatments for bullous pemphigoid (BP). There is evidence to suggest that topical application may be associated with a lower risk of mortality. However, there is a lack of comprehensive large-scale data comparing mortality rates, as well as the risk of major adverse cardiac events (MACE), infections and relapse, between systemic and topical corticosteroid treatments. To evaluate the risk of death, MACE, infections and relapse in patients with BP treated with systemic or topical corticosteroids. A population-based retrospective cohort study was performed using the TriNetX US Collaborative Network. As a measure against bias, propensity score matching for age, sex, 10 diseases and 6 medications was done, and 3 sensitivity analyses were conducted. All-time risk of death was increased in US patients with BP exposed to any dose of systemic corticosteroids (n = 2917) vs. patients treated with topical clobetasol propionate [n = 2932; hazard ratio (HR) 1.43, 95% confidence interval (CI) 1.28-1.58 (P < 0.001)]. This was consistent in time-stratified analysis (1- and 3-year mortality rates) and in analysis contrasting prednisone (equivalent) doses of 1-10 mg (low) or 30-100 mg (medium-high) systemic corticosteroid to topical treatment. The increased risk of death in US patients with BP exposed to any dose of systemic corticosteroids vs. topical treatment was accompanied by increased risks for MACE (HR 1.33, 95% CI 1.08-1.64; P = 0.008) and infections (HR 1.33, 95% CI 1.15-1.54; P < 0.001). The risk of continued disease or relapse was decreased in patients treated with systemic vs. topical corticosteroids (HR 0.85, 95% CI 0.77-0.94; P = 0.002). Results regarding mortality and continued disease or relapse persisted in three sensitivity analyses. Potential limitations included the retrospective data collection, bias for treatment selection and miscoding. Pending validation in prospective studies, where feasible - and despite the heightened risk of relapse - topical corticosteroid treatment may be advantageous over systemic corticosteroid treatment owing to its significantly lower risk of death.

#1739 Combination rituximab &amp; low-dose IV cyclophosphamide induction therapy for severe multi-system eosinophilic granulomatosis with polyangiitis

Abstract Background and Aims Current guidelines advise rituximab (RTX) or cyclophosphamide treatment for organ-threatening disease in eosinophilic granulomatosis with polyangiitis (EGPA). However, conventional treatment is often limited by partial efficacy, toxicity, high relapse rate and steroid dependency. We investigate the use of a combined RTX, low-dose cyclophosphamide, and steroid regimen for treatment of severe EGPA. Method Single-centre retrospective cohort study of patients treated with a combination induction regimen for severe EGPA (with kidney, cardiac or neurological involvement) between 2012-23. Data reported as median (±IQR) Results Eighteen patients (10 male; age 56 years [52-62]) are included. At treatment, BVAS was 16.3 [14-20], peak eosinophil count 9.3 × 109/L [5-13], C-reactive protein (CRP) 122 mg/L [80-193]. Eleven cases were ANCA positive (10 MPO-, 1 PR3-ANCA.) The proportions of patients affected by active/new respiratory, ENT, neurological, and gastrointestinal disease were 18/18 (100%), 14/18 (78%), 11/18 (61%), and 1/18 (6%), respectively. 11/18 (61%) had cardiac involvement (troponin 10345 ng/L [1240-7621]) and 6/18 (33%) had necrotising glomerulonephritis confirmed by renal biopsy (creatinine 123 µmol/L [83-167]). Cumulative cyclophosphamide dose was 3.5g [3.0-3.5] and total RTX dose was 2g. Initial prednisolone dose was 0.5-1.0 mg/kg/day, and this was rapidly weaned to 5 mg daily at a median time of 6.1 months [3.9-7.2], and 9/18 (50%) had steroids withdrawn completely by 11.7 months [4.6-20.6]. First-line maintenance treatment was azathioprine or MMF. By 6 months, all achieved disease remission as assessed by BVAS (all 0) and improved laboratory parameters: CRP 1 mg/L, eosinophil count 0.1 × 109/L, and ANCA testing negative. In those with renal disease, kidney function improved or stabilised in all (creatinine 95 µmol/L). In those with cardiac disease (11/18), magnetic resonance imaging was performed at baseline and at follow up (median time of 3.7 months) in all patients. Of these, 9/11 (82%) had oedema on initial scan and this improved in all cases; 10/11 (91%) had late gadolinium enhancement at baseline, which persisted in every case, though with significantly lower burden. The median follow-up period was 38 months [14-55]. At 1, 3 and 5 years, 100%, 92% and 76% of patients were in sustained remission (Fig. 1A). Three patients experienced relapse; one patient had major relapse with skin involvement requiring reinduction treatment; two patients had minor ENT relapse requiring retreatment with glucocorticoids. Infection-free survival at 1, 3 and 5 years was 94%, 78%, 62%, respectively (Fig. 1B). There were no deaths. Conclusion This regimen provided rapid disease control in patients with severe multi-system EGPA, including those with life-threatening cardiac manifestations, and enabled rapid glucocorticoid tapering and withdrawal. Disease-free remission was sustained during long-term follow up. Combination induction regimens may have a role in the treatment of organ-threatening disease in EGPA.

Association between duration of antidepressant treatment for major depressive disorder and relapse rate after discontinuation: A meta-analysis

The optimal duration of antidepressant treatment for patients with major depressive disorder to reduce the risk of relapse after discontinuation remains uncertain. Medline, Cochrane Central Register of Controlled Trials, and Embase were systematically searched for randomized controlled trials (RCTs) with a discontinuation design. A single-group summary meta-analysis was performed to calculate 6-month relapse rates after discontinuation. Meta-regression with restricted cubic splines was performed to model the non-linear relationship between treatment duration and relapse rate after discontinuation. Thirty-five RCTs were included. The relapse rate after discontinuation was approximately 34.81 % at 6 months and 45.12 % at 12 months. After controlling for covariates, the meta-analysis shows that the duration of treatment is associated with the risk of relapse after discontinuation in a non-linear curve, with a relatively higher risk of relapse observed for a duration of less than three months. There appears to be no further reduction in the risk of relapse when treatment is continued for over six months. Our results indicate the importance of at least three months of treatment to avoid the relatively high risk of relapse after discontinuation. The additional benefit of longer treatment remains to be proven.

The Effectiveness of Mindfulness-Based Cognitive Therapy for Major Depressive Disorder and Relapse Prevention

Due to the prevalence and severity of Major Depressive Disorder (MDD), it is essential to examine the effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) when treating and preventing the recurrence of MDD. This paper evaluated recent research in this area. First, this article described the importance of research on MDD, which has led to considering MBCT techniques for treating MDD. In addition, this article presented previous literature which explored the symptoms and causes of MDD, as well as the mechanisms and theories of mindfulness training and Cognitive Behavioral Therapy (CBT). Moreover, the paper reviewed recent findings in this area and compared the overall effectiveness of MBCT, Active Control Condition (ACC), and medical therapy when treating MDD. Plus, this paper identified the core components of MBCT, including self-compassion cultivation, meditation training, attentional bias improvement, and meta-cognitive skill enhancement. Finally, this paper also proposed that future research should involve large and diverse samples, longer-term studies, subgroup analyses, and qualitative research to understand MBCT’s effectiveness and applications more comprehensively.

Assessment of Surgical Difficulty in Patients with Rectal Cancer—The Impact of Pelvimetry

Background: Low-quality tumoral surgical excision is the major relapse factor in rectal cancer. If the surgery is highly difficult, the quality of the resection might be compromised. In the literature, it is described how low pelvic dimensions can make this type of surgery difficult. The main aim was to study the influence of pelvic measures in surgical difficulty on the patients submitted to tumoral surgical resection with curative intent. Methods: A retrospective, observational and analytic study was conducted. A total of 73 patients over a period of 3 years were included. Demographic and surgical data, as well as measurements of the pelvis taken from MRI, were collected. An univariate and multivariate analysis was performed. Results: 11 (15.1%) patients were classified as having highly difficult surgeries. All 11 patients were male. Significant differences were found between groups regarding gender (p = 0.013), transverse diameter of the pelvis (p &lt; 0.001), interspinal distance (p = 0.014) and intertuberous distance (p &lt; 0.001). The logistic regression revealed that a small transverse diameter (O.R. 0.919, 95% I.C. 0.846–0.999, p = 0.047) increases the degree of difficulty of the surgery. Conclusions: Male patients with a small pelvic measurement deserve a thorough surgical plan that predicts a quality resection.

Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials

ObjectiveTo compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated...

A Wegner's Granulomatosis Risk Prediction Model Based on Machine Learning Algorithms

Introduction: Prediction of Wegener's granulomatosis diagnosis and relapse is a complex process. In this study, we applied machine learning algorithms to predict Wegener's granulomatosis relapse.&#x0D; Methods: In this research, 189 patients admitted to Amiralam Hospital were studied and followed for approximately 2 years. Patient features included demographics, organ involvement, symptoms, and other clinical data. Different popular machine learning algorithms were applied for predicting Wegener's granulomatosis relapse, including Support Vector Machines, Random Forest, Gradient Boosting, and XGBoost algorithms. The prediction model performance was measured for the different candidate prediction algorithms using accuracy, precision, recall, and F1-measure. The selected prediction model performance was calculated based on different relapse rates and major relapse occurrence according to Birmingham Vasculitis Activity Score (BVAS) fields.&#x0D; Results: Applying different machine learning algorithms, the XGBoost algorithm performed the best. The results indicated that the prediction model's performance increased when calculating higher relapse rate possibilities. The XGBoost model had 82% accuracy while predicting more than one relapse rate and 92% accuracy in predicting more than twice the relapse rate. We also calculated the SHAP value for the prediction model. The results indicated that Cr, BVAS, lymphocyte percentage, vitamin D, nose involvement, alkaline phosphatase, diagnosis age, white blood cell count, erythrocyte sedimentation rate, and initial nose presentation are the 10 most important features according to SHAP value.&#x0D; Conclusion: In this study, we have developed Wegener's granulomatosis relapse prediction model using machine learning algorithms. We achieved reasonable precision and recall for early prediction and decision- making regarding Wegener's granulomatosis relapse.

Exploration of the optimal time to discontinue propranolol treatment in infantile hemangiomas: A prospective study

BackgroundRelapse of infantile hemangiomas (IHs) after withdrawal from propranolol treatment is common. Early withdrawal is believed to increase the risk of relapse. ObjectiveTo determine the optimal time to discontinue propranolol treatment for IHs. MethodsA prospective study conducted at a tertiary referral center. ResultsCompared to withdrawal after 1-month maintenance treatment, withdrawal after 3-months maintenance, corresponding achieving maximum regression of IHs, was associated with a lower major relapse rate (P=0.041). The relapse (P=0.055) and adverse event rates (P=0.154) between the two withdrawal modes were not statistically significant. Compared with direct withdrawal, the relapse (P=0.396), major relapse (P=0.963), and adverse event rates (P=0.458) of gradual withdrawal were not statistically different. Patients with/without relapse could be best distinguished according to whether withdrawal followed a 3-months maintenance and age >13 months (AUC=0.603). Patients with/without major relapse could be best distinguished according to whether withdrawal was accompanied by 3-months maintenance (AUC=0.610). LimitationsNon-randomization and single-center design. ConclusionsThe optimal propranolol withdrawal time to avoid relapse is when the patient is aged >13 months and the lesion has maintained for 3 months after reaching maximum regression, while the optimal time to prevent major relapse is after 3 months of maintenance.

Single Cell RNA Sequencing Enables Identification of Mantle Cell Lymphoma Subclones with Drug-Resistant Profiles Already at Diagnosis and May be Used for Therapy Prognostication and Personalization

Mantle cell lymphoma (MCL) is a chronically relapsing B cell lymphoproliferative malignancy characterized by translocation t(11;14)(q13;q32), cyclin D1 overexpression and significant chromosomal instability. One of the main hypotheses of MCL relapses is a clonal evolution driven by therapy selection of subpopulations carrying adverse genetic and epigenetic aberrations. Our previous whole exome sequencing analysis of 25 MCL tumors showed that the majority of the detected single-nucleotide variants and copy number variants (CNV) were already detectable at diagnosis. To further analyze the subclonal structure of MCL at diagnosis and clonal evolution at relapse, we implemented single cell RNA sequencing analysis of five patients with MCL at diagnosis and at the first clinical relapse after failure of standard immunochemotherapy. All analyzed patients achieved at least partial remission. Fresh-frozen tumor cells were sorted to obtain Hoechst − CD45 + population which was processed using single cell 3′ protocol (10X Genomics). The libraries were paired-end sequenced on Novaseq 6000 (Illumina). The reads were aligned to GRCh38 human genome. The MCL cells were distinguished from the normal B cells based on of CCND1 expression and unsupervised clustering. CNVs were predicted using inferCNV package. These CNVs shared a high degree of similarity with the CNVs predicted using available exome sequencing data. The t-SNE representation of the data clearly showed unique positions for the malignant lymphocytes obtained from each of the five analyzed patients ( Figure 1a). In contrast, non-malignant cells (T cells, B cells and monocytes) have grouped together irrespective of the patient or compartment of origin ( Figure 1b). These data suggest two conclusions. First, each patient's malignant cells have unique genetic background. Second, the impact of the microenvironment does not override the impact of the genetic makeup of the non-malignant cells. The data thus suggest comparability of the malignant cells obtained from different compartments. Hierarchical clustering of the per-cell CNV profiles revealed subclonal heterogeneity of the MCL population in all analyzed compartments both at diagnosis and at relapse. In all analyzed patients the clustering identified several large subclones with significant differences (DG L) and at least one minor subclone (DG S) with significant similarities compared to the major clone detectable at relapse (R L). These data suggest that the majority of the diagnostic MCL cells (i.e., DG L clones) were indeed eliminated by therapy, which on clinical level corresponded to achieving remission. On the other hand, the data also suggest that MCL cells with CNV profiles highly similar to the major relapse clone (i.e., R L) were detectable already at diagnosis (i.e., DG S, Figure 1c). To gain a better insight into the biology of the DG S clones with potential drug-resistant phenotype, we analyzed transcriptome differences between DG S and DG L clones. For each patient we identified different sets of significantly upregulated genes in DG S compared to DG L. These included genes coding for important cell surface molecules ( MARCKS, CD52, CD79A, LTB), regulators of cell motility and cytoskeleton dynamics ( STMN1, SWAP70, CFL1, TUBB, TUBA1B, TMSB4X), transcription factor PRDM2, energy metabolism proteins ( MT-ND4, MT-CO1, ATP5MG), protein degradation proteins ( UBA52, PSMC4, UFD1, UBE2L3) and others. Among these genes, significant upregulation of TMSB4X, SWAP70, HLA-A, TUBB4B, RPS26, UBA52, PSMB2, SNRPG, ARPC1B, ATP5MG was detected in three out of five patients. Many of these genes code for oncogenes involved in cell motility and aggressiveness. To further characterize subclonal clusters in MCL population we used marker gene detection and subsequent gene set enrichment analysis, which identified cell adhesion molecules as major category upregulated in four out of five patients in clusters associated with relapse. Our data shows the applicability of the single cell genomic approaches not only to analyze subclonal heterogeneity for the study of disease biology, but also to identify drug-resistant subclones at diagnosis, predict response to various types of therapies thereby enabling therapy personalization. Acknowledgement: Supported by Grant Agency of the Czech Republic GA23-05474S and National Institute for Cancer Research (EXCELES) LX22NPO5102.

Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicentre service evaluation in England.

The National Health Service in England funds 12 months of weekly subcutaneous tocilizumab (qwTCZ) for patients with relapsing or refractory giant cell arteritis (GCA). During the COVID-19 pandemic, some patients were allowed longer treatment. We sought to describe what happened to patients after cessation of qwTCZ. Multicentre service evaluation of relapse after stopping qwTCZ for GCA. The log-rank test was used to identify significant differences in time to relapse. 336 GCA patients were analysed from 40 centres, treated with qwTCZ for a median (interquartile range, IQR) of 12 (12-17) months. At time of stopping qwTCZ, median (IQR) prednisolone dose was 2 (0-5) mg/day. By 6, 12 and 24 months after stopping qwTCZ, 21.4%, 35.4% and 48.6% respectively had relapsed, requiring an increase in prednisolone dose to a median (IQR) of 20 (10-40) mg/day. 33.6% of relapsers had a major relapse as defined by EULAR. Time to relapse was shorter in those that had previously also relapsed during qwTCZ treatment (P = 0.0017); in those not in remission at qwTCZ cessation (P = 0.0036); and in those with large vessel involvement on imaging (P = 0.0296). Age ≥65, gender, GCA-related sight loss, qwTCZ treatment duration, TCZ taper, prednisolone dosing, and conventional synthetic DMARD use were not associated with time to relapse. Up to half our patients with GCA relapsed after stopping qwTCZ, often requiring a substantial increase in prednisolone dose. One third of relapsers had a major relapse. Extended use of TCZ or repeat treatment for relapse should be considered for these patients.

Association between plasma rituximab concentration and the risk of major relapse in antineutrophil cytoplasmic antibody-associated vasculitides during rituximab maintenance therapy.

Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes. Patients included in the MAINRITSAN2 trial (NCT01731561) were randomized to receive a 500 mg fixed-schedule RTX infusion or an individually-tailored regimen. Rituximab plasma concentrations at month 3 (CM3 ) were assessed. DNA samples (n=53) were genotyped for single nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models. One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 μg/mL) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% vs. 18.0%; p=0.02, respectively). Low RTX plasma concentration at 3 months (CM3 <4 μg/mL) was an independent risk factor for major relapse (odds ratio=6.56; 95% CI 1.26-34.09; p=0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 μg/mL as an independent risk factor for major relapse (Hazard ratio [HR] = 4.81; 95% CI 1.56-14.82; p=0.006) and relapse (HR=2.70; 95% CI 1.02-7.15; p=0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28. These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase. This article is protected by copyright. All rights reserved.

Retrospective Analysis of the Burden of Illness of Eosinophilic Granulomatosis With Polyangiitis (EGPA) Versus Asthma in Commercially Insured US Patients.

Background andaim Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder associated with the presence of blood and tissue eosinophilia, extravascular granulomas, and asthma. Currently, the burden of EGPA on the patient and the healthcare system is not well characterized. This study aimed to assess the real-world clinical and economic burden of disease in adult patients with EGPA compared with matched patients with asthma without EGPA. Methods This retrospective cohort study used medical, pharmacy, enrolment, and demographic data from a US administrative claims database (PharMetrics Plus). Patients ≥18 years old, with ≥six months of continuous health plan enrolment in the baseline period, and ≥12 months of continuous health plan enrolment in the follow-up period were eligible for this analysis. Patients with EGPA and patients with asthma without EGPA were identified using diagnosis codes and were subsequently matched 1:5 (e.g., one patient with EGPAmatched with five patients with asthma, without EGPA) based on baseline characteristics. The primary outcome measure was all-cause healthcare costs; secondary outcomes included healthcare resource utilization, medication usage, and clinical characteristics. Results In the final matched cohorts, there were 7183 patients with EGPA and 35,915 patients with asthma without EGPA. During the follow-up period, mean total all-cause healthcare costs were significantly higher in patients with EGPA than in those with asthma without EGPA (mean {standard deviation}: $44,405 {$82,060} vs $24,487 {$54,691}; p<0.0001). Patients with EGPA had mean total all-cause healthcare costs that were 73.9% greater than those in patients with asthma without EGPA, even after applying a multivariable analysis to adjust for differences in demographic and clinical characteristics. Medication usage was consistently higher in the EGPA population than in the asthma population (excepting short-acting β2-agonists). The majority of patients in the EGPA population (83.1%) also experienced ≥one relapse during the study period, with 26.3% of patients in the EGPA population experiencing a major relapse. Conclusions There is a significantly greater economic and clinical burden associated with EGPA compared with asthma without EGPA in adults. These results underscore the unmet need in this patient population for improved disease control strategies that will reduce the burden of EGPA on patients and the healthcare system.

Development of Acute Promyelocytic Leukemia in a Patient with Granulomatosis with Polyangiitis: A Case Report.

Granulomatosis with polyangiitis (GPA) is a rare disorder of unknown etiology, which is characterized by necrotizing granulomatous inflammation of the upper respiratory system and kidneys. Immunosuppressive treatment (cyclophosphamide or azathioprine with glucocorticoids) improved the outcome of GPA, however, latent comorbidity (cancers and hematologic malignancies) has become more prevalent in recent years. Here, we present a first case of the patient with GPA complicated by acute promyelocytic leukemia (APL) successfully treated with molecular-targeted therapy. A 77-year-old female was referred to our hospital for nasal obstruction, hearing loss, and fever. Otorhinolaryngological investigation revealed otitis media, and head computed tomography (CT) showed paranasal mucosal thickening with septal perforation. Chest CT showed cavitary granulomatous lesions in both lungs. Biopsy of the nasal mucosa revealed granulomatous lesions, and the patient was finally diagnosed with GPA. Oral administration of prednisolone 50 mg/day was initiated, and oral azathioprine (50 mg/day) was added. After 26 months of azathioprine initiation, pancytopenia developed and azathioprine was stopped. Then sudden elevated levels of blasts appeared in the hemogram (blasts 11%). She was diagnosed with APL via bone marrow examination which revealed plenty of faggot cells with Auer rods and chromosomal mutation. The patient was started on all-trans retinoic acid 60 mg/day following arsenic trioxide 7 mg/day in consideration of elderly onset. Complete remission was achieved and oral prednisolone was successfully reduced to 15 mg/day without a major relapse of GPA. Because GPA can be complicated by APL even during maintenance treatment using azathioprine, careful monitoring should be performed in such patients.

Adding low dose cyclophosphamide to rituximab for remission-induction may prolong relapse-free survival in patients with ANCA vasculitis: A retrospective study

ObjectiveRituximab (RTX) and cyclophosphamide (CYC) are effective remission-induction therapies in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, combining these therapies may favor prognosis in patients with a major disease presentation. We conducted a retrospective study to compare patients treated with a combination of RTX and low dose CYC (RTX-CYC) or with RTX only, both followed by tailored maintenance with RTX, with regard to long-term outcomes. MethodsPatients treated in the Maastricht University Medical Center between March 2007 and January 2019, were screened for eligibility. The primary outcome variable was major relapse rate after two and five years. Secondary outcome variables were clinical data and laboratory parameters. ResultsOf the 246 screened patients, 34 received RTX-CYC and 28 RTX only for remission-induction. All patients were followed for at least two years, with a median follow-up of 48 months (IQR 24–60). At baseline, renal involvement was more prevalent in the RTX-CYC patients (85% vs. 61%, P = 0.028). Major relapse rates within two years, but not after five years, were significantly lower in the RTX-CYC group (3% vs. 24%, P = 0.032). The rate of infections, hypogammaglobulinemia, end-stage renal disease, malignancies, and mortality did not differ after two and five years. ConclusionAdding low dose CYC to RTX is safe and may prevent major relapses in patients with severe AAV in the first two years after remission-induction. Randomized controlled trials that compare the efficacy and safety between RTX and a combination of RTX with CYC are needed.

Long-term outcome and relapse patterns in Ewing sarcoma patients with extensive lung/pleural metastases after a complete response to systemic therapy.

BackgroundEwing sarcoma (ES) is sensitive to systemic therapy, including chemotherapy and anti-angiogenesis Tyrosine Kinase Inhibitors(aaTKIs). However, the prognosis of patients with metastatic disease remains poor. Recurrence or distant metastasis after a complete response (CR) or near-CR due to systemic therapy is not rare.MethodsWe reviewed data from 187 ES patients between 2014–2019 treated at a single institute in China. Patients with extensive lung/pleural metastases (L/Pmeta) who had a CR or near-CR after first- or second-line chemotherapy with or without aaTKIs were retrospectively enrolled. Event-free survival (EFS) and overall survival (OS) were determined using the Kaplan–Meier method. For patients who had L/P recurrence, images were reviewed to define the exact location of each recurrent lesion, compared with the primary L/P lesion before chemotherapy and summarized as the relapse pattern.ResultsSeventeen patients and 21 cases of CR/nCR (5 by VDC/IE, 3 by VIT, and 13 by AVI) were finally analyzed. Median follow-up for surviving patients was 39.6 (range, 14.5–60.9) months. Median EFS and OS were 9.3 (95% confidence interval [CI], 2.0–16.6) months and 37.5 (95% CI, 21.8–53.1) months, respectively. The 2-year EFS was 19% and the 2-year OS was 70.6%, respectively. Most patients (82.4%) received whole lung irradiation (WLI). Lung/pleural relapse occurred in 71.4% (15/21) of CR/nCR cases. Most notably, all recurrent lesions exactly coincided with the original metastatic lesions before chemotherapy (exactly in situ) in 9 of the 15 recurrent cases, which was thus the major relapse pattern, whereas 42.9% had distant metastases other than L/Pmeta.ConclusionsSurvival of ES patients with extensive L/Pmeta remains poor, even if they have a CR after systemic therapy. Recurrence exactly in situ is the major relapse pattern. WLI is not sufficient to prevent local recurrence in lung or pleura. More aggressive local treatment for metastatic lesions is warranted.

MO259: Maintenance Therapies for Anti-Neutrophil Cytoplasmic Antibody Small-Vessel Vasculitis: A Network Meta-Analysis

Abstract BACKGROUNDS AND AIMS Over the past two decades, considerable progress has been made in maintaining remission in patients with anti-neutrophil cytoplasmic antibody (ANCA) vasculitis using a variety of medications, including rituximab, azathioprine, mycophenolate, methotrexate, and glucocorticoids. However, although survival has improved dramatically over the last decades, relapse rates remain significant for certain patients, stressing the need for advocation of new therapeutic strategies. The aim of this study was to compare the efficacy and safety of different regimens used for maintenance of remission in patients with ANCA-vasculitis. METHOD This network meta-analysis studied adult patients with ANCA-vasculitis in complete remission, who were maintained with various regimens, excluding patients with eosinophilic granulomatosis with polyangiitis, and those who have ended up in end-stage kidney disease. Outcomes of interest included relapse (any/major), relapse-free survival and adverse effects. PubMed, Scopus, Web of Science, CENTRAL, Clinicaltrials.gov and Google Scholar were systematically searched from inception. RESULTS Overall, the meta-analysis was based on 10 reports, describing the outcomes of 7 RCTs including 752 patients with ANCA-vasculitis. Compared with rituximab, relapse-free survival was significantly worse with the use of azathioprine {HR 2.11 [95% confidence interval (CI) 1.19–3.74]}, methotrexate [HR 2.51 (95% CI 1.24–5.08)] and mycophenolate mofetil [HR 3.57 (95% CI 1.70–7.46)]. Compared with mycophenolate mofetil, better outcomes were estimated for azathioprine [HR 0.59 (95% CI 0.37–0.94)], cyclophosphamide [HR 0.39 (95% CI 0.20–0.75)] and leflunomide [HR 0.30 (95% CI 0.11–0.84)]. Compared with rituximab a higher relapse risk was estimated for azathioprine [OR 2.15 (95% CI 1.00–4.59)] and mycophenolate mofetil [OR 4.42 (95% CI 1.63–11.94)]. A higher risk of major relapse was calculated for azathioprine [OR 2.39 (95% CI 1.10–5.19)], methotrexate [OR 3.18 (95% CI 1.14–8.89)] and mycophenolate mofetil [OR 5.20 (95% CI 1.65–16.37)] compared with rituximab. The rates of serious adverse effects did not differ significantly among interventions. CONCLUSION Rituximab appears predominant in maintaining remission in patients with ANCA-vasculitis with no cost in adverse events.

A Meta-Analysis of the Safety and Efficacy of Maintenance Therapies for Antineutrophil Cytoplasmic Antibody Small-Vessel Vasculitis

IntroductionTo compare the efficacy and safety of different regimens used for maintenance of remission in patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis.MethodsThis network meta-analysis studied adult patients with ANCA vasculitis in complete remission, who were maintained with various regimens, excluding patients with eosinophilic granulomatosis with polyangiitis (GPA) and those who have ended up in end-stage kidney disease. Outcomes of interest included relapse (any/major), relapse-free survival, and adverse effects. PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Google Scholar were systematically searched from inception.ResultsOverall, the meta-analysis was based on 10 reports, describing the outcomes of 7 randomized controlled trials (RCTs) including 752 patients with ANCA vasculitis. Relapse-free survival was significantly worse with the use of azathioprine (hazard ratio [HR]: 2.11, 95% CI: 1.19–3.74), methotrexate (HR: 2.51, 95% CI: 1.24–5.08), and mycophenolate mofetil (HR: 3.57, 95% CI: 1.70–7.46) compared with the use of rituximab. Outcomes estimated for azathioprine (HR: 0.59, 95% CI: 0.37–0.94), cyclophosphamide (HR: 0.39, 95% CI: 0.20–0.75), and leflunomide (HR: 0.30, 95% CI: 0.11–0.84) were better than those for mycophenolate mofetil. When examining relapse-free survival, relapses were more likely with use of azathioprine (odds ratio [OR]: 2.15, 95% CI: 1.00–4.59) and mycophenolate mofetil (OR: 4.42, 95% CI: 1.63–11.94) compared with the use of rituximab. The risk of major relapse calculated for azathioprine (OR: 2.39, 95% CI: 1.10–5.19), methotrexate (OR: 3.18, 95% CI: 1.14–8.89), and mycophenolate mofetil (OR: 5.20, 95% CI: 1.65–16.37) was higher than that for rituximab. The rates of serious adverse effects did not differ significantly among interventions.ConclusionRituximab appears predominant in maintaining remission in patients with ANCA vasculitis with no cost in adverse events.

Different Types of ANCA Determine Different Clinical Phenotypes and Outcome in ANCA-Associated Vasculitis (AAV).

AimAccumulating evidence supports the use of antineutrophil cytoplasmic antibody (ANCA) type to classify different clinical entities. We aimed to evaluate whether the presence and type of ANCA determine different diseases, based on clinical phenotypes, renal involvement, and response to treatment.Patients and MethodsDifferences in terms of clinical manifestations, disease activity, laboratory parameters, and histology were recorded between patients with focal necrotizing glomerulonephritis (FNGN) due to myeloperoxidase (MPO-), proteinase 3-ANCA(+) [PR3-ANCA(+)], and ANCA(-) disease at time of diagnosis. Patients were treated with the same protocol and followed-up for 24 months, in a scheduled basis of every month for the first year and every 3 months for the second year. Primary end points were: (i) Combined end-stage renal disease (ESRD) and/or death and (ii) The presence of major or minor relapse during follow-up and secondary endpoint was the combination of ESRD and reduction of estimated glomerular filtration rate (eGFR) ≥ 50%.ResultsA total of 92 patients (M/F 39/53, mean age 59.1 ± 15 years) diagnosed with FNGN due to ANCA-associated vasculitis (AAV), 36 (39.1%) patients diagnosed with PR3-ANCA, 39 (42.4%) patients diagnosed with MPO-ANCA, and 17 (18.5%) patients diagnosed with ANCA(-) were included. Number of involved systems differed significantly between PR3-, MPO-ANCA, and ANCA(-), with only renal involvement in 3, 25.5, and 29% of patients, two systems involved in 33, 31, and 59% of patients, and > 3 systems involved in 64, 43.5, and 12% of patients, respectively (p = 0.002). Histology classification revealed focal, crescentic, mixed, and sclerotic type in 14, 64, 19, and 3% of PR3-ANCA(+), 8, 28, 18, and 46% of MPO-ANCA, and 41, 29, 6, and 24% of ANCA(-), respectively (p < 0.0001). Primary end point of ESRD ± Death was reached in 11 (30.6%), 16 (41%), and 6 (35.5%) patients with PR3-ANCA(+), MPO-ANCA(+), and ANCA(-), respectively (p = NS); similarly, ESRD± > 50% eGFR reduction in 8 (22.2%), 15 (38.5%), and 5 (29.4%) patients, respectively (p = NS), meaning that patients with MPO-ANCA(+) showed a propensity to decline renal function. Rate of relapse was increased in the presence of patients with PR3-ANCA(+), 14 (38.9%), 4 (11.8%), and 2 (10.3%) of patients with PR3-ANCA(+), MPO-ANCA(+), and ANCA(-), had at least one relapse during the two-year follow-up (p = 0.006).ConclusionClinical phenotype and renal histology differ significantly between PR3-ANCA(+), MPO-ANCA(+), and ANCA(-) disease and FNGN; however, renal function outcome is similar, despite the increased rate of relapses in patients with PR3-ANCA(+).

Axonal Demyelination Leading to Neurologic Impairment: A Review Study of Multiple Sclerosis (MS)

Introduction: Multiple Sclerosis (MS) is a central nervous system auto-immune condition signaled and marked by inflammatory action which leads primarily to demyelination resulting in neurologic impairments. This condition is more common in genetically-disposed individuals and individuals who have had a history of Epstein–Barr virus (EBV) infection&#x0D; Aim: The study's aim is to examine recent knowledge on the etiology and clinical manifestations of multiple sclerosis, as well as diagnostic testing and recent management options that are being explored to improve the living conditions of people living with Multiple Sclerosis.&#x0D; Method: This review article focuses on research studies that have relevant, up-to-date and current therapies employed in the management of individuals living with Multiple Sclerosis. It also includes research studies that take a look at Multiple Sclerosis from the viewpoint of the caretaker&#x0D; Results: In this review, it can be seen that the most common clinical manifestation include cognitive impairment, fatigue, psychiatric impairments. The prevalence of Multiple Sclerosis is closely associated with a history of Epstein–Barr virus (EBV) infection as well as genetic predisposition. Pharmacological therapy has been proven to reduce the incidents of a major relapse but hasn’t been advised for patients with a mild relapse. Physical therapy has been proven to be effective when individualized but this is not cost-effective. It has been advised for patients with a mild relapse and for patients undergoing pharmacological therapy, however there is a drawback – physical of therapy can only be administered by very qualified professionals and there is a scarcity of these professionals.&#x0D; Conclusion: Physical Therapy in conjunction with pharmacological therapy, with further improvements, can drastically improve the quality of lives for people living with Multiple Sclerosis.

Cost-Effectiveness of Rituximab (Fixed Schedule vs Tailored Dose) Compared With Azathioprine Maintenance Therapy in Adults With Generalized Antineutrophil Cytoplasm Antibody-Associated Vasculitis in Colombia

ObjectivesAzathioprine has been the therapy of choice for the maintenance of remission in patients with antineutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis, but recent studies show that rituximab could be more effective. To evaluate the cost-effectiveness of azathioprine, fixed-schedule rituximab, and tailored-dose rituximab for ANCA-associated systemic vasculitis. MethodsA Markov model from the perspective of the Colombian healthcare system was designed with annual cycles and a 5-year time horizon, charting the following states: remission, minor relapse, major relapse, and death. The discount rate was 5%. Transition probabilities were obtained from a systematic literature review. The costs (1 US dollar = 2956 Colombian pesos in 2018) were estimated based on national drug registries and official fee manuals for procedures, along with other resources. The main outcomes were quality-adjusted life-years (QALYs) taken from the Tufts registry. Univariate and multivariate sensitivity analyses were performed. ResultsFinal costs were $1446 for azathioprine, $4898 for tailored-dose rituximab, and $6311 for fixed-schedule rituximab. QALYs gained were 3.18, 4.08, and 3.98, respectively. Rituximab was cost-effective (cost per incremental QALY gained: $4919, and $6865), and tailored-dose administration had a lower cost. Sensitivity analyses did not affect the results. ConclusionsTailored-dose rituximab was the most cost-effective treatment for ANCA-associated vasculitis. Azathioprine presented worse effectiveness and lower cost, and fixed-schedule rituximab was dominated by tailored-dose rituximab.