The retinoic acid receptor co-factor NRIP1 is uniquely upregulated and represents a therapeutic target in acute myeloid leukemia with chromosome 3q rearrangements

Aberrant expression of Ecotropic Viral Integration Site 1 (EVI1) is a hallmark of acute myeloid leukemia (AML) with inv(3) or t(3;3), which is a disease subtype with especially poor outcome. In studying transcriptomes from AML patients with chromosome 3q rearrangements, we identified a significant upregulation of the Nuclear Receptor Interacting Protein 1 (NRIP1) as well as its adjacent non-coding RNA LOC101927745. Utilizing transcriptomic and epigenomic data from over 900 primary patient samples as well as genetic and transcriptional engineering approaches, we have identified several mechanisms that can lead to upregulation of NRIP1 in AML. We hypothesize that the LOC101927745 transcription start site harbors a context-dependent enhancer that is bound by EVI1, causing upregulation of NRIP1 in AML with chr3 abnormalities. Furthermore, we show that NRIP1 knockdown negatively affects the proliferation and survival of 3q-rearranged AML cells and increases their sensitivity towards ATRA, suggesting that NRIP1 is relevant for the pathogenesis of inv(3)/t(3;3) AML and could serve as a novel therapeutic target in myeloid malignancies with 3q abnormalities.

Circulating miRNAs as Potential Biomarkers Distinguishing Relapsing–Remitting from Secondary Progressive Multiple Sclerosis. A Review

Multiple sclerosis (MS) is a debilitating neurodegenerative, highly heterogeneous disease with a variable course. The most common MS subtype is relapsing–remitting (RR), having interchanging periods of worsening and relative stabilization. After a decade, in most RR patients, it alters into the secondary progressive (SP) phase, the most debilitating one with no clear remissions, leading to progressive disability deterioration. Among the greatest challenges for clinicians is understanding disease progression molecular mechanisms, since RR is mainly characterized by inflammatory processes, while in SP, the neurodegeneration prevails. This is especially important because distinguishing RR from the SP subtype early will enable faster implementation of appropriate treatment. Currently, the MS course is not well-correlated with the biomarkers routinely used in clinical practice. Despite many studies, there are still no reliable indicators correlating with the disease stage and its activity degree. Circulating microRNAs (miRNAs) may be considered valuable molecules for the MS diagnosis and, presumably, helpful in predicting disease subtype. MiRNA expression dysregulation is commonly observed in the MS course. Moreover, knowledge of diverse miRNA panel expression between RRMS and SPMS may allow for deterring disability progression through successful treatment. Therefore, in this review, we address the current state of research on differences in miRNA panel expression between the phases.

Features of late-onset systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, characterized by multiorgan involvement, most commonly targeting the skin, joints and kidneys. Late-onset disease occurs in patients over the age of 50 and represents a diagnostic challenge, as it is less frequently encountered and it may exhibit a more unusual clinical and paraclinical picture. The aim of this paper is to highlight two cases of SLE diagnosed in female patients of considerably advanced ages, 81 and 72 years respectively, in order to enhance physician awareness with regard to this distinct disease subtype.

Combination of Bone Marrow Biopsy and Flow Cytometric Analysis: The Prognostically Relevant Central Approach for Detecting Bone Marrow Invasion in Diffuse Large B-Cell Lymphoma

Bone marrow (BM) involvement is associated with prognosis in diffuse large B-cell lymphoma (DLBCL), the most prevalent disease subtype of malignant lymphoma. We conducted this multi-institutional retrospective study to investigate the functional association and prognostic values of four BM tests (BM biopsy, BM clot, flow cytometry (FCM), and BM smear). A total of 221 DLBCL patients were enrolled. BM involvement was detected in 17 (7.7%), 16 (7.2%), 27 (12.2%), and 34 (15.4%) patients by BM biopsy, BM clot, FCM, and BM smear, respectively. The consistency between BM biopsy and clot examination was favorable, with a κ coefficient of 0.705, whereas the consistencies among other modalities were poor. In 184 patients treated with the first-line R-CHOP (-like) regimen, BM involvement was associated with shorter progression-free survival (PFS) irrespective of the type of modality for a positive result. Intriguingly, among various single and combinatory modalities, the combination of BM biopsy and FCM had the highest hazard ratio of 3.33 and a c-index of 0.712. In conclusion, our study suggested that the combination of BM biopsy and FCM is the prognostically relevant central approach for BM involvement detection. The other BM examinations also may provide complementary information in clinical settings.

Patient-Reported Symptom Severity in a Nationwide Myasthenia Gravis Cohort: Cross-sectional Analysis of the Swedish GEMG Study

Objectives:To describe Myasthenia Gravis-Activities of Daily Living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort.Methods:In a cross-sectional prevalent cohort study, the Genes and Environment in Myasthenia Gravis study (GEMG), performed November 2018 - August 2019, Myasthenia gravis (MG) patients were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early onset MG (EOMG, <50 years), late onset MG (LOMG, ≥50 years) or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sex and different MG-ADL scores.Results:A total of 1077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n=1035) ranged from 0-18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity and diagnostic delay (OR=1.62, 1.72 and 1.69, Padj=0.017, 0.013 and 0.008) and inversely correlated with high educational attainment (OR=0.59, Padj=0.02), but not with age at inclusion, disease subtype nor disease duration. Almost half the population (47%) reported MG-ADL ≥3p, corresponding to an unsatisfactory symptom state.Conclusions:In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, we observe that almost half of patients report current disease symptoms associated to an unsatisfactory symptom state, indicating the need for improved treatment options.

AB0736 JUVENILE IDIOPATHIC ARTHRITIS IN ADULTHOOD: TRENDS OF THE DISEASE AND SOCIO-PROFESSIONAL FUTURE

Background:Juvenile idiopathic arthritis (JIA) is the most common arthropathy of childhood that may lead to physical disability and reduced quality of life, thus hindering the ability of the patients to achieve a meaningful adult life.Objectives:The aim of this study was to assess the trends of the disease and socio-professional future.Methods:We conducted a retrospective study including adult patients aged > 18 years with a history of JIA according to the International League of Associations for Rheumatology (ILAR). Collected data included age, sex, the characteristics of the disease (subtype of JIA, disease duration). The level of education, marital status as well as the profession were recorded.Results:The study included 32 patients with a female perdominance: sex ratio was 1,5. The mean age was 29,5 years old [18-64]. The mean age of onset of the disease was 6 years and 2 months [2-17]. The frequency of each JIA subset was at follows: polyarticular with rheumatoid factor (n= 14), polyarticular without rheumatoid factor (n=9), systemic (n= 2), enthesitis-related arthritis (n=7), oligoarthritis (n= 5). Four patients suffered from bilateral cataract due to corticosteroid intake. Polyarticular RF+ and RF- progressed into an authentic seropositive and seronegative RA in 71.4% and 66.7% respectively. Among oligoarticular subtype, an extension of the disease to a polyarticular FR+ form (n=1) and to a seronegative rheumatoid arthritis (n=1) was noted. Systemic JIA forms remained in remission with an articular involvement. All the patients with ERA developed spondylarthritis. Although forty–two percent of the patients were married, only half of them had children. Ten percent of patients stopped attending school because of disease flares and deformation. A university level was found in 16% of cases. Only Thirty patients had a profession. Of the patients, 74.4% had received disease-modifying anti-rheumatic drugs (DMARDs) and 36.3% of them were still taking a DMARD. Ten patients were on biologics. Severe disability was found in 20% of patients and concerned mainly the hip (57,2%), the wrist (28,5%) and the elbows (14,3%). Prosthetic joint replacement was found in 2% of cases with a revision of the latter in one patient.Conclusion:Adults with JIA often have significant levels of disability, usually related to severe joint complications. There is a clear requirement for a better transition to adulthood and a socio-professional rehabilitation.Disclosure of Interests:None declared

Single dose of BNT162b2 mRNA vaccine against SARS-CoV-2 induces high frequency of neutralising antibody and polyfunctional T-cell responses in patients with myeloproliferative neoplasms

Encouraging results have been observed from initial studies evaluating vaccines targeting the novel beta coronavirus which causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, concerns have been raised around the efficacy of these vaccines in immunosuppressed populations, including patients with haematological malignancy. Myeloproliferative neoplasms (MPN), in particular myelofibrosis (MF), are associated with heterogenous immune defects which are influenced by patient age, disease subtype and the use of cytoreductive therapies. Patients with a WHO defined diagnosis of an MPN presenting to our clinic were recruited following first injection of 30μg BNT162b2. A positive anti-S IgG ELISA was seen in 76.1% (16) of patients following vaccination with positive neutralising antibodies detected in 85.7% (18) of patients. A memory T cell response was observed in 80% (16) of patients, with a CD4+ T cell response in 75% (15) and a CD8+ T cell response in 35% (7). These results, for the first time, provide some reassurance regarding the initial immune response to the BNT162b2 vaccine amongst patients with MPN, with response rates similar to that observed in the general population.