Severe Relapse Research Articles

Impact of graft-versus-host disease prophylaxis on immune reconstitution in patients after allogeneic hematopoietic stem cell transplantation

The graft-versus-host disease (GVHD) is among the most common complications after hematopoietic stem cell transplantation (allo-HSCT). The main tools for GVHD prevention remain calcineurin inhibitors (cyclosporin A, tacrolimus), methotrexate, mycophenolate mofetil. Upon implementation of reduced-intensity conditioning regimens, antithymocyte globulin was widely introduced. However, negative effects upon reconstitution of T-cell immunity have been noted, thus increasing risk of severe infectious complications and disease relapse. With extended practice of HSCT from alternative (partially matched or haploidentical) donors, cyclophosphamide was increasingly used. Our aim was to study reconstitution of immune cell subpopulations in the patients undergoing bone marrow transplantation (BMT), when using different GVHD prophylaxis regimens, including the schedules with post-transplant CP usage. The study concerned 44 cases classified into 2 groups. The first one included patients with standard immunosuppressive therapy, antithymocyte therapy, cyclosporine A, methotrexate, mycophenolate mofetil. The second group included the patients who received CP as immunosuppressive drug combined with other treatments (cyclosporine A, methotrexate, mycophenolate mofetil). At specified control terms, (D+14, +30, +60, +90) the blood leukocyte subpopulations were assayed by means of multicolor flow cytometry. Absolute counts of CD4+ cells in HSCT recipients treated with CP post-BMT proved to be sufficiently lower at D+14 and +30, than in those treated with classical immunosuppressive therapy. However, at later terms, (D+60, +90), these differences were not observed. Moreover, in CP-treated bone marrow recipients, absolute numbers of CD8+cells was significantly higher, compared to the patients who received conventional GVHD prophylaxis. Reconstitution of the studied lymphocyte populations in hematopoietic cell recipients did not depend on the GVHD prophylaxis regimen. Usage of CP combined with bone marrow as a source of stem cells, brings about sufficient decrease of some cell populations (CD4+; CD8+; NK cells) at early terms post-transplant. Administration of CP combined with hematopoietic stem cells as the source of hematopoietic graft seems to be more reasonable.

Monitoring of Patients with Autoimmune Cytopenias during Sars-Cov-2 Vaccination Campaign: The Experience of a Reference Center

▪SARS-CoV-2 infection and vaccination have raised concern in immune mediated diseases, including autoimmune cytopenias (AIC, i.e. autoimmune hemolytic anemia, AIHA; autoimmune thrombocytopenia, ITP; autoimmune neutropenia, AIN; aplastic anemia, AA; and their combination, termed Evans syndrome, ES). The latter are highly heterogeneous conditions with variable severity and a clinical course marked by several relapses often triggered by immune-activating events (infections, traumas, surgery, etc.) including vaccines. Some reports of ITP and AIHA post-SARS-CoV-2 vaccines have been described but no population studies have been conducted in AIC patients. Here we systematically studied a large series of 100 patients with AIC (44 AIHA, 38 ITP, 7 AIN, 6 ES, and 5 AA) prospectively followed at a reference center in Milan, Italy, who underwent SARS-CoV-2 vaccination from 24 th of March until the end of June 2021. Patients (median age 62 years, range 25-89, female/male ratio 1.7) were monitored with whole blood counts and LDH testing the week before and the week after each vaccination dose. Importantly, ongoing AIC therapy (38% of cases, including steroids, cyclosporine, eltrombopag, and complement inhibitor sutimlimab) were kept stable within the 2 weeks before vaccination. Patients mainly received Pfizer-BioNtech vaccine (N=88), followed by Moderna (N=10), and Astra-Zeneca (N=2). Table 1 summarizes hematologic trends and side effects observed after each dose in patients with ITP and AIHA. Regarding the former, a delta percentage reduction of 10% or higher was observed in up to 13% of cases after the first and the second dose, requiring therapy adjustment in 2 patients. They were two elderly male subjects on low dose eltrombopag treatment and experienced a severe/moderate relapse (platelets 28 and 21x10^9/L) with mucosal bleeding, after the 2 nd dose of Pfizer vaccine. Both had a concomitant trigger (1 hip fracture and 1 bronchitis reactivation) and were rescued by increasing eltrombopag dose and with the addition of prednisone 1 mg/Kg day. Regarding AIHA, 3 elderly patients experienced a clinically significant relapse (>10% Hb decrease): 1 female patient experienced an Hb reduction from 10.4 to 9.1 g/dL after the first dose of Pfizer vaccine, that required a slight increase of steroid dose (to 5 mg day prednisone) and remained stable after the second dose; 1 male subject had an Hb reduction from 13.9 to 9.1 g/d>L after the first dose of Moderna vaccine, requiring prednisone 0.5 mg/kg day; the third male patient experienced a severe relapse (Hb reduction by 47%, from 14 to 7.4 g/dL) with LDH increase to 2.3 x ULN after the second dose of Pfizer vaccine. The patient required high dose intravenous steroids and hemolysis improved in about 1 week. All patients had warm type AIHA and had complained no other triggers or non-hematologic adverse events. Patients with AIN, AA and ES had no significant changes in their hematologic values (1 AIN had a neutrophil decrease by 30% but was consistent with previous oscillations; 2 ES had a platelet or neutrophil decrease within the normal range) and required no treatment changes. Finally, the following non-hematologic adverse events were observed: fever (7%), pain at the injection site (15%) and arthralgia (<5%), without significant differences between the first and the second dose.These data show that SARS-CoV-2 vaccination may be associated with a mild decrease of hematologic values in about 10% of AIC cases. However, true ITP and AIHA relapses occurred in 5% of cases only, sometimes in the presence of a concomitant trigger, and were rapidly rescued with treatment adaptation. Overall, the hematologic monitoring of SARS-CoV-2 vaccine adopted in our survey appears appropriate to early detect and manage AIC reactivation, ensuring a safe vaccination campaign in this patient population. [Display omitted] DisclosuresFattizzo: Annexon: Consultancy; Alexion: Speakers Bureau; Kira: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barcellini: Novartis: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria; Agios: Honoraria, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

Autoimmune Cytopenias and Covid-19 Vaccination: Relapse and Suggested Treatment

Introduction:There are “de novo” and relapsed autoimmune diseases in patients with COVID-19 that includes autoimmune thrombocytopenia, Evans syndrome and autoimmune hemolytic anemia among others (Hematology 2021;26:225-239 and Curr Rheumatol Rev 2021;17:193-204). There is scanty material about relapse of autoimmune hematological diseases after vaccination for COVID-19 (Blood Adv 2021;13:2794-2798).Material and methods:Adult patients 18 years or older with autoimmune thrombocytopenia, Evans syndrome and autoimmune hemolytic anemia who completed SARS-Cov2 vaccination.Results:Between December 2020 and June 2021 there were identified 53 patients with autoimmune hematological disease that completed SARS-Cov2 vaccination. Thirty-six with autoimmune thrombocytopenia, all were preexisting. Twelve with autoimmune hemolytic anemia, 5 secondaries to previous COVID-19 and 7 preexisting. Five with Evans syndrome, all preexisting.Twenty-three patients with autoimmune thrombocytopenia did not develop any fall in the platelet count. Ten patients had a fall of 50 % from basal counts and recovered spontaneously. Three patients developed counts below 30,000 with purpuric symptoms and needed treatment that consisted in two courses of dexamethasone 40 mg daily for four days every three weeks; all patients reached complete remission without any further treatment.All patients with Evans syndrome developed hemolysis and low platelet counts. Two patients maintained Hb levels above 10 and platelet counts above 50,000; both patients had spontaneously recovery. Three patients developed Hb levels below 7 with anemic syndrome and platelets below 50,000 but without purpuric syndrome; they received the same treatment as patients with autoimmune thrombocytopenia and reached complete remission too.All five patients with autoimmune hemolytic anemia secondary to COVID-19 developed Hb levels below 7 with anemic symptoms and needed treatment as described. The remaining 7 patients with preexisting autoimmune anemia developed hemolysis; five with Hb levels above 7 and recovery without any treatment; two had Hb levels below 7 and received the same treatment with full recovery and complete remission.Conclusions:Autoimmune cytopenias can be trigger by vaccines and viral infections by involving molecular mimicry and circulating immune complexes, including SARS-Cov2. The viral protein spike from SARS-Cov2 has mimicry between the Ankyrin-1 in the erythrocyte surface, and has been linked as one of the pathogenesis pathways of autoimmune hemolytic anemia secondary to COVID-19 (Br J Haematol 2020;190:e92-e93 and Blood 2020;136:suppl8,138001). Relapse of autoimmune cytopenias after vaccination with SARS-Cov2 involves stimulation of autoantibodies production from preexisting B cells. Although relapses were observed in the three kinds of patients, all with hemolytic component developed a drop in the hemoglobin levels, most of them needed treatment. It is important to notice that patients with hemolytic autoimmune anemia secondary COVID-19 had severe relapse, event that support the mimicry mentioned lines above. It is important to follow up closely this kind of patients after SARS-CoV2 vaccination, we suggest weekly complete blood counts, and a short courses of high dose dexamethasone can induce curable responses if treatment is advised. DisclosuresNo relevant conflicts of interest to declare.

Dissection of Bone Marrow Microenvironment By Single Cell RNA Sequencing in Warm AIHA Patients: A Proof-of-Concept Analysis

Warm type autoimmune hemolytic anemia (wAIHA) is a rare disease characterized by variable severity and bone marrow (BM) compensation, unpredictable relapses and several complications (i.e. infections and thrombosis). Most therapies are aimed at restoring immune tolerance by targeting various immunologic mechanisms (autoantibody production, reticuloendothelial phagocytosis, and complement activation). BM composition during acute and chronic/relapsing disease phases is still under investigated, and preliminary studies showed that it may predict anemia severity and treatment response.We aimed at dissecting BM environment by single cell RNA sequencing (scRNA-seq) in patients with wAIHA. We selected 2 patients experiencing mild hemolytic reactivations handled with low dose steroids (M-AIHA) and 2 with severe relapses requiring high steroid doses and rituximab (S-AIHA). We focused on lymphoid/myeloid subpopulations and their gene expression and evaluated the association of output data with clinical features.We performed scRNA-seq for 17,989 single cells, detecting over 23,446 expressed genes per cell on average. Uniform manifold approximation and projection (UMAP), a method for nonlinear dimensionality reduction, showed the microenvironmental cell composition, including T-, B- and NK- lymphocytes and their subpopulations, plasma cells, CD14+ and CD16+ monocytes, hematopoietic stem cells, and myeloid precursors (Figure 1A). On the whole, BM microenvironment showed a high frequency of innate immunity effectors such as NK cells and monocytes (11% and 15% of total cells), likely reflecting the inflammatory state typical of autoimmune/autoinflammatory response. T-cell subpopulations were also highly represented. Specifically, more CD4+ memory than CD4+ naïve T-cells (58% vs 38%) were found, and T-regs represented a small fraction (4%). Also, CD8+ memory cells were more frequent than CD8+ naïve and CD8+ effectors (55% vs 24% vs 21%). Both CD8+ memory and effectors type 2 cells were higher than type 1 cells, indicating a likely participation of T cell compartment in disease phenotype. Finally, B cells were particularly underrepresented, probably due to recent therapy (steroids/rituximab). Figure 1B displays % of BM immune cells divided into M-AIHA and S-AIHA. S-AIHA patients showed higher CD14+ monocytes (57% vs 43%) and decreased NK cells (19% vs 81%) as compared to M-AIHA. Interestingly, within the latter compartment, the CD56 bright NKs were over-represented in S-AIHA (83% vs 17%), suggesting an attempt to negatively regulate activated lymphocytes. Moreover, S-AIHA showed a severe decrease of B cells as compared to M-AIHA, consistently with more recent rituximab treatment. Furthermore, we performed differential expression and gene set enrichment (GSEA) analysis within the different cell subset comparing M-AIHA and S-AIHA. Concerning T cells, we found differential expression of genes related to T-cell receptor, immunoglobulins and interferon alpha/gamma response. Regarding CD14+ monocytes, we observed a downregulation of pathways related to immunomodulatory/inflammatory cytokines, complement activation and apoptosis in S-AIHA versus M-AIHA. Finally, using the CopyKat tool, we found aneuploidies in myeloid cells, including stem cells, suggesting that the selective pressure from the immune environment may lead to accumulation of genetic lesions in chronic S-AIHA. This clonal evolution can possibly explain the clinical overlap with myeloid neoplasms.Overall, these preliminary data show for the first time that scRNA-seq technology is feasible in wAIHA patients and gives insights in the pathogenic role of bone marrow immunologic microenvironment. Additionally, BM composition appears to dynamically modify according to disease severity and treatment, potentially enabling tailored therapies. [Display omitted] DisclosuresFattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bolli: Celgene/BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Honoraria. Barcellini: Alexion Pharmaceuticals: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria.

Einblicke in die Behandlung der Multiplen Sklerose mit Cladribin-Tabletten seit Beginn der COVID-19-Pandemie

Der Prävention von Infektionskrankheiten kommt bei der Multiplen Sklerose (MS) eine besondere Bedeutung zu, da diese den Krankheitsverlauf ungünstig beeinflussen können. Dies wird uns im Rahmen der COVID-19-Pandemie verdeutlicht, wo die SARS-CoV-2-Infektion als Auslöser von besonders schweren und prolongierten Schüben und klinischer Verschlechterung identifiziert werden konnte. Umso wichtiger ist es daher, den Einfluss der für die MS zugelassenen Immuntherapien auf eine etwaige Suszeptibilität für eine SARS-CoV-2-Infektion, den COVID-19-Krankheitsverlauf und das Impfansprechen zu verstehen. In dieser Übersichtsarbeit werden diese Punkte unter besonderer Berücksichtigung von Cladribin-Tabletten, einer für den hochaktiven MS-Verlauf zugelassenen Immunrekonstitutionstherapie, beleuchtet.

De Novo and Relapsing Glomerulonephritis following SARS-CoV-2 mRNA Vaccination in Microscopic Polyangiitis

Vaccination against SARS-CoV-2 is the most important advance in the fight against the ongoing coronavirus pandemic. Recent case reports show that the SARS-CoV-2 vaccines can very rarely cause de novo or relapsing glomerular disease. Here, we report two female patients with microscopic polyangiitis, who developed severe glomerulonephritis after immunisation with the BNT162b2 mRNA vaccine. One patient with a possible ongoing but undiagnosed disease developed severe necrotising glomerulonephritis after the second vaccination. In the other patient with a long-lasting disease, rituximab maintenance therapy had been postponed because of the coronavirus pandemic. She noted macrohematuria immediately after the second vaccine dose and developed a severe renal relapse leading to end-stage kidney disease. We suggest that patients with ANCA-associated vasculitis be carefully monitored for disease activity immediately before and after receiving the SARS-CoV-2 vaccination, especially if maintenance therapy has been interrupted. Ultimately, mRNA vaccines should probably be avoided in these patients.

Genetic Variants of DMBT1 and SFTPD and Disease Severity in Paediatric Inflammatory Bowel Disease-A Polish Population-Based Study.

Deleted in malignant brain tumours 1 protein (DMBT1) and surfactant protein D (SFTPD) are antimicrobial peptides previously linked to inflammatory bowel disease (IBD) susceptibility. This study attempts to link the most potential IBD-associated polymorphisms in DMBT1 and SFTPD with the disease severity in children. A total of 406 IBD patients (Crohn’s disease (CD) n = 214 and ulcerative colitis (UC) n = 192) were genotyped using hydrolysis probe assay. Clinical expression was described by disease activity scales, albumin and C-reactive protein levels, localisation and behaviour (Paris classification), systemic steroid, immunosuppressive, biological, and surgical treatment, number of exacerbation-caused hospitalisations, relapses and nutritional status. IBD patients with the risk genotype (AA) in DMBT1 rs2981804 had more frequent biological treatment (AA: vs. AG/GG; p = 0.012), concomitant diseases (AA vs. AG vs. GG; p = 0.015) and cutaneous manifestations (AA vs. AG/GG, p = 0.008). In UC, rs2981804 genotypes might be linked with albumin concentrations at diagnosis (AA vs. AG vs. GG; p = 0.009). In CD, DMBT1 rs2981745 was significantly associated with the number of severe relapses per year of disease (p = 0.020) and time-to-immunosuppression (p = 0.045). SFTPD was seemingly found to be associated with age at first immunosuppression in IBD (CC vs. CT vs. TT; p = 0.048). In conclusion, selected polymorphisms of DMBT1 and SFTPD might be associated with some disease severity measures in children with IBD. However, the magnitude of associations and their clinical relevance might be minor.

Paediatric MS

Pediatric MS (i.e. disease onset before 18 years) shares many characteristics with adult-onset MS. However, children with MS have higher relapse and new MRI lesion rates than adults. They tend to have more severe relapses, with better recovery, but still develop disability at a younger age than adult-onset MS. Pediatric MS has the potential for irreversible central nervous system injury especially as it is still maturing. Differential diagnoses include ADEM, NMO and MOG-associated disease, among others.

SARS‐CoV‐2 vaccination in patients with autoimmune cytopenias: The experience of a reference center

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Impact of yoga and physical exercise on psychological wellbeing among substance abusers: a randomized controlled trial.

Substance use disorder is a pattern of recurrent use of illicit substances that leads to severe psychosocial imbalance and recurrent relapse. The study was to evaluate the efficacy of a yoga-based intervention as an add-on in enhancing psychological wellbeing, compared with physical exercise among substance abusers. In this randomized controlled study, 96 male participants with substance use disorder from a residential rehabilitation treatment center, Kathmandu, Nepal, were randomly allocated into two groups namely the yoga group (n=48, mean age±SD=25.18±6.43) and the physical exercise group (n=48, mean age±SD=25.02±5.02). The participants in the yoga group attended the 90min yoga sessions for 12weeks (sixdays per week) whereas the physical exercise group attended exercise sessions for the same duration. Above mentioned interventions were in addition to standard rehabilitation treatment. The study measured the Self-Control, Anxiety, Depression, Sleep parameters, and Mindfulness at the baseline and after 12weeks of intervention. A significant enhancement in self-control was observed in both the yoga (p<0.033, d=0.33) and the exercise group (p<0.038, d=0.32). Yoga group showed significant improvement in mindfulness score (p<0.017, d=0.37), whereas exercise group did not show any significant changes in mindfulness (p<0.169, d=0.21). The depression and anxiety scores reduced significantly in both yoga (p<0.044, d=0.31; p<0.025, d=0.35 resp.) and exercise (p<0.032, d=0.34. p<0.039, d=0.32. resp.) group. Furthermore, significant reduction was seen in sleep disturbance after yoga (p<0.001, d=0.52) and exercise (p<0.001, d=0.78) intervention. The sleep- somnolence score reduced significantly only in yoga group (p<0.020, d=0.36). The magnitude of improvement was higher in the yoga group than physical exercise group on self-control, mindfulness, depression, anxiety and some sleep parameters, however the between group differences could not reach to the level of significance. The 12week yoga intervention did not appear to be significantly more effective than the 12week physical exercise program on psychological wellbeing in male participants with substance use disorder. However, greater improvement in psychological wellbeing was observed within the yoga group. In future, a multi-centric study with robust design, larger sample size and longer follow-up is required to conform the present results and to find out the difference between the impacts of yoga and physical exercise on psychological wellbeing in substance abusers.

Real-world survey of pneumonitis and its impact on durvalumab consolidation therapy in patients with non-small cell lung cancer who received chemoradiotherapy after durvalumab approval (HOPE-005/CRIMSON)

ObjectivesThe incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown. Materials and methodsWe retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019. ResultsMedian age was 70 (range: 40–87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P < 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study’s rechallenge criteria and did not experience a severe pneumonitis relapse. ConclusionHigh V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study’s rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.

New series of Kuhnt'y operations (extirpatio tarsi) for trachoma

In 1894 prof. Kuhnt performed the first operation to remove cartilage in a patient who suffered from frequent and severe relapses of pannus.

A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/CFS

A significant proportion of COVID-19 patients are suffering from prolonged Post-COVID-19 Fatigue Syndrome, with characteristics typically found in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, no clear pathophysiological explanation, as yet, has been provided. A novel paradigm for a Post-COVID-19 Fatigue Syndrome is developed here from a recent unifying model for ME/CFS. Central to its rationale, SARS-CoV-2, in common with the triggers (viral and non-viral) of ME/CFS, is proposed to be a physiologically severe stressor, which could be targeting a stress-integrator, within the brain: the hypothalamic paraventricular nucleus (PVN). It is proposed that inflammatory mediators, released at the site of COVID-19 infection, would be transmitted as stress-signals, via humoral and neural pathways, which overwhelm this stress-center. In genetically susceptible people, an intrinsic stress-threshold is suggested to be exceeded causing ongoing dysfunction to the hypothalamic PVN's complex neurological circuitry. In this compromised state, the hypothalamic PVN might then be hyper-sensitive to a wide range of life's ongoing physiological stressors. This could result in the reported post-exertional malaise episodes and more severe relapses, in common with ME/CFS, that perpetuate an ongoing disease state. When a certain stress-tolerance-level is exceeded, the hypothalamic PVN can become an epicenter for microglia-induced activation and neuroinflammation, affecting the hypothalamus and its proximal limbic system, which would account for the range of reported ME/CFS-like symptoms. A model for Post-COVID-19 Fatigue Syndrome is provided to stimulate discussion and critical evaluation. Brain-scanning studies, incorporating increasingly sophisticated imaging technology should enable chronic neuroinflammation to be detected, even at a low level, in the finite detail required, thus helping to test this model, while advancing our understanding of Post-COVID-19 Fatigue Syndrome pathophysiology.

Therapeutic inertia in relapsing-remitting multiple sclerosis

BackgroundTherapeutic inertia (TI) is defined as a failure to initiate or intensify treatments despite evidence of disease activity. Its prevalence and determining factors in Relapsing-Remitting Multiple Sclerosis (RRMS) patients in Portugal are not known. The main objective of this work was to ascertain the prevalence of TI in RRMS and its determining factors. MethodsWe conducted a multicentre retrospective observational study of RRMS patients followed in MS Clinics of six Portuguese hospitals with at least one medical appointment in 2018. TI was defined as the absence of treatment initiation or intensification when therapeutic goals were unmet, that is when there was evidence of disease activity based on the definition of “no evidence of disease activity” (NEDA) which refers to absence of clinical relapses, absence of disease progression measured by expanded disability status scale (EDSS) and absence of new disease activity (new T2 lesions/enhancing lesion) on magnetic resonance imaging (MRI) over the period of observation. ResultsWe included 427 patients with RRMS meeting inclusion criteria, 69.6% females, with a mean age of 41.66 years old. The mean age at diagnosis was 33.17 years old and the average number of years since diagnosis was 8.72. MS relapses were reported on 54 patients. Moderate to severe relapses were reported in 59.3%. Median EDSS score was 1.5. Intention to get pregnant was explicit in 39 patients, representing 18.8% of the women at childbearing age. Among the 365 patients who had an MRI, 23.8% had new T2 lesions and 7.4% had enhancing lesions. Regarding DMT, 72.8% were treated with interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate, 20.6% were under fingolimod, natalizumab, rituximab, and cladribine, and the remaining 6.6% were without treatment. Adverse events were reported in 12.9% of patients, and 10.1% mentioned preferences regarding the treatment. TI was present in 80 (18.7%) patients, representing 54.8% of those with potential to inertia. Patients with a radiologically less active disease, who were already on a DMT and who had no adverse events from their current treatment were more likely to have TI (p<0,05). Also, patients followed in centers classified as higher level of care (level 1) had more TI compared with patients followed in centers of levels 2 and 3. ConclusionTI was present in 1 in 5 patients, exceeding half of the sample with the potential to inertia, corroborating the high prevalence of TI in other studies. The determining factors of TI were the absence of relapses or the occurrence of mild relapses, being already on DMT, absence of adverse events, and follow-up in higher care level centers. TI is a topic rarely addressed in MS and this work highlights the importance of therapeutic optimization in these patients. Further studies should be held to explore the factors that influence TI once they have a great impact on therapeutic decisions.

Risk Factors Predicting Graft-Versus-Host Disease and Relapse-Free Survival (GRFS) after Allogeneic Hematopoietic Stem Cell Transplantation in Relapse/Refractory Non-Hodgkin Lymphomas

Although the increasing of novel drugs has improved the survival outcomes with non-Hodgkin lymphoma (NHL), about 50% of them have failed to respond or relapse and small fraction only could be cured by autologous hematopoietic stem cell transplantation (autoHSCT). So, allogeneic hematopoietic stem cell transplantation (alloHSCT) considers as a definitive modality of cure for relapsed or refractory NHL. However, it still associated with problematic concerns including graft-versus-host disease (GVHD), relapse, and non-relapse death. The success of alloHSCT is based on the measurement of survival duration with clinically significant negative events such as a novel composite endpoint of GVHD and relapse-free survival (GRFS) where the events were acute GVHD grade 3-4, moderate to severe chronic GVHD, relapse or death. Based on these reasons, we assessed GRFS and attempt to identify the prognostic factors of GRFS in patients with relapse/refractory NHL.MethodsWe retrospectively analyzed a consecutive 82 adult patients with relapse/refractory NHL who received an alloHSCT as salvage purpose between January 2008 and March 2016.ResultsMedian age at alloHSCT and follow-up duration were 38 (19-65) years and 28 months (1-112 months), respectively. 73 patients (89%) in aggressive histologic subgroup, 37 patients (45.1%) of bone marrow involvement, and favorable disease status as CR/PR at alloHSCT was in 45 patients (54.9%). 32 patients (65%) were received autoHSCT prior to alloHSCT. Majority (n=78, 95%) received reduced intensity conditioning regiemens, and donor type was HLA matched related (n=27, 33%), matched unrelated (n=45, 55%) and haploidentical (n=10, 12%).The 3-year overall survival (OS), progression-free survival (PFS), the cumulative incidence of relapse (CIR), and cumulative incidence of non-relapse mortality (CI of NRM) were 50.9%, 44.4%, 34.8%, and 20.0%, respectively. Also, the 1-year OS, PFS, CIR, and CI of NRM were 66.7%, 56.8%,19.7% and 17.3%, respectively, and the 1-year GRFS was 40.7% in the group of all relapse/refractory NHL. By the multivariate analysis, received more than the third-line chemotherapy before the transplant, high IPI scoring at diagnosis, and unfavorable disease status as stable disease/ progressive disease at alloHSCT were associated with a worse GRFS at 1-year post alloHSCT (HR 1.88, p=0.045; HR 1.92, p=0.025; HR 1.94, p=0.024).ConclusionGRFS is a useful endpoint that is worth investigating tool as a maker of favorable HCT in lymphoma. These data suggest that the early adaptation of alloHSCT in the group of chemosensitive relapse with low-risk IPI score provide the highest GRFS rates as successful HCT in relapse/refractory NHL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Does the mental health system provide effective coverage to people with schizophrenic disorder? A self-controlled case series study in Italy

PurposeTo measure indicators of timeliness and continuity of treatments on patients with schizophrenic disorder in ‘real-life’ practice, and to validate them through their relationship with relapse occurrences.MethodsThe target population was from four Italian regions overall covering 22 million beneficiaries of the NHS (37% of the entire Italian population). The cohort included 12,054 patients newly taken into care for schizophrenic disorder between January 2015 and June 2016. The self-controlled case series (SCCS) design was used to estimate the incidence rate ratio of relapse occurrences according to mental healthcare coverage.ResultsPoor timeliness (82% and 33% of cohort members had not yet started treatment with psychosocial interventions and antipsychotic drug therapy within the first year after they were taken into care) and continuity (27% and 23% of patients were persistent with psychosocial interventions, and antipsychotic drug therapy within the first 2 years after starting the specific treatment) were observed. According to SCCS design, 4794 relapses occurred during 9430 PY (with incidence rate of 50.8 every 100 PY). Compared with periods not covered by mental healthcare, those covered by psychosocial intervention alone, antipsychotic drugs alone and by psychosocial intervention and antipsychotic drugs together were, respectively, associated with relapse rate reductions of 28% (95% CI 4–46%), 24% (17–30%) and 44% (32–53%).ConclusionHealthcare administrative data may contribute to monitor and to assess the effectiveness of a mental health system. Persistent use of both psychosocial intervention and antipsychotic drugs reduces risk of severe relapse.

Impact of COVID-19 on psychiatric services and presentations in north-west Edinburgh

AimsCOVID-19 has had a significant impact on healthcare provision, accessibility and psychiatric presentations. We aim to investigate the impact of the pandemic on psychiatric services and the severity of presentations in Edinburgh, with a particular focus on the North-West Edinburgh Community Mental Health Team (NW CMHT).MethodMeasures of the impact of the pandemic on NW CMHT were identified as referral numbers from primary care and Did Not Attend (DNA) rates. Royal Edinburgh Hospital admissions, detentions under the Mental Health (Care and Treatment) (Scotland) Act 2003 (MHA) and Out of Hours (OOH) contacts were used as proxy measures to explore the severity and urgency of presentations.Quantitative data focussing on these parameters for patients aged 18–65 years in NW CMHT in 2019 and 2020 were collected from NHS Lothian Analytical Services. OOH data were only available Edinburgh-wide. All data were anonymised in line with NHS Lothian Information Governance Policy.In order to assess the impact on staff, a questionnaire was created and disseminated, with qualitative data returned anonymously.ResultReferrals to NW CMHT decreased by 9.3% in 2020 (n = 2164) compared to 2019 (n = 2366). Referrals in April (n = 81) and May (n = 102) 2020 were far below the monthly average across the two years (n = 188).Appointment numbers were very similar in 2019 (n = 3542) and 2020 (n = 3514). Despite this, DNA and cancellation rates decreased by 3.94% in 2020. Questionnaire results illustrated some of the challenges for staff of working during a pandemic.Admissions to hospital reduced by 6.8% in 2020 (n = 219 vs n = 235). While MHA detentions in NW Edinburgh increased by only 1.8% (n = 173 vs n = 170), new Compulsory Treatment Orders (CTO) increased by 60%. Furthermore, OOH contacts across Edinburgh increased by 45.2% when compared to 2019.ConclusionThe COVID-19 pandemic altered the way patients accessed healthcare. Uncertainty of the public in accessing primary care services early in the pandemic may have contributed to reduced referral numbers.The increase in CTOs is suggestive of severe relapses in previously stable patients or new episodes of illness. The pandemic may have contributed to a reduction in early recognition, and referral, of those with major mental disorders resulting in more protracted or severe illness episodes. The increase in OOH crisis contacts supports such a hypothesis.Despite what would be expected, DNA and cancellation rates in NW CMHT reduced. The contribution of telemedicine to this warrants further exploration as a means of delivering healthcare in an efficient and accessible way.

Plasma exchange with COVID-19 convalescent plasma in a patient with severe ANCA-associated vasculitis and COVID-19 pneumonia after rituximab therapy.

ABSTRACTThe combination of coronavirus disease 2019 (COVID-19) pneumonia and pulmonary–renal syndrome due to ANCA‐associated vasculitis (AAV) poses diagnostic uncertainty and a therapeutic dilemma. According to current limited knowledge of COVID-19, the application of commonly used drugs in AAV, cyclophosphamide (CYC) and rituximab (RTX), must be weighed carefully in active COVID-19 infection. We report a case of a 52-year-old male patient with concurrent severe COVID-19 pneumonia and acute relapse of pulmonary–renal syndrome due to AAV after recent RTX maintenance dose. The patient presented with severe hypoxaemia, complete B-cell depletion and severe acute respiratory syndrome coronavirus 2 viraemia. He was successfully treated with therapeutic plasma exchange employing COVID-19 convalescent plasma.

Civil commitment for opioid misuse: do short-term benefits outweigh long-term harms?

In response to a sharp rise in opioid-involved overdose deaths in the USA, states have deployed increasingly aggressive strategies to limit the loss of life, including civil commitment—the forcible detention...

An impact of air pollution on moderate to severe relapses among multiple sclerosis patients

BackgroundMultiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system with both a genetic and environmental component. ObjectiveIn the current study, we examined an association between incidence of MS moderate to severe relapses and exposure to air pollutants and meteorological exposures. MethodsWe enrolled MS patients in Southern Israel during 2000-2017. Exposure assessment relied on satellite-based model of exposure to particulate matter of size <2.5 and 10 microns (PM2.5, PM10) and temperature at a spatial resolution of 1 km (Kloog et al., 2015). The information on exposure to nitrogen dioxide (NO2), sulfur dioxide (SO2) and ozone (O3) levels was completed from the database of the monitoring stations. We analyzed the data using a semi-ecological approach. The monthly incidence of MS-related relapses requiring hospitalization as a function of environmental factors was analyzed by time-series technique, adjusting to sex, age and smoking. We also used a case-crossover approach to compare environmental exposure of a patient on the day of the relapse with the exposure on the relapse-free days. All estimates were adjusted to the heat index and were divided by IQR. ResultsThere were 287 MS patients in the study, with an average age of 52.8 ± 16.7 years, 37% of them (107) being under 40. Mostly female (66.2%), and 13.6% of the patients smoking (47% non-smoking and 39.4% unknown). PM2.5 was independently associated with MS relapses within the non-smoking population [Relative Risk (RR)=1.28, 95%CI:1.01-1.62]. O3 was found adversely associated with MS relapses among patients younger than 40 [RR=1.58, 95%CI 1.03-4.43]. Based on the case-crossover approach, relapses were associated with elevated levels of PM10 and NO2 in all subjects [Odds Ratio (OR)=1.05, 95%CI:1.00-1.11; OR=1.85, 95%CI: 1.28-2.68, respectively]. An adverse association with PM2.5 was observed in non-smokers [OR 1.12, 95%CI 1.00-1.25]. ConclusionsThe findings show that MS relapses are adversely associated with an ambient exposure to PM and NO2.