Symptomatic Treatment Research Articles

Dengue virus exploits autophagy vesicles and secretory pathways to promote transmission by human dendritic cells.

Dengue virus (DENV), transmitted by infected mosquitoes, is a major public health concern, with approximately half the world's population at risk for infection. Recent decades have increasing incidence of dengue-associated disease alongside growing frequency of outbreaks. Although promising progress has been made in anti-DENV immunizations, post-infection treatment remains limited to non-specific supportive treatments. Development of antiviral therapeutics is thus required to limit DENV dissemination in humans and to help control the severity of outbreaks. Dendritic cells (DCs) are amongst the first cells to encounter DENV upon injection into the human skin mucosa, and thereafter promote systemic viral dissemination to additional human target cells. Autophagy is a vesicle trafficking pathway involving the formation of cytosolic autophagosomes, and recent reports have highlighted the extensive manipulation of autophagy by flaviviruses, including DENV, for viral replication. However, the temporal profiling and function of autophagy activity in DENV infection and transmission by human primary DCs remains poorly understood. Herein, we demonstrate that mechanisms of autophagosome formation and extracellular vesicle (EV) release have a pro-viral role in DC-mediated DENV transmission. We show that DENV exploits early-stage canonical autophagy to establish infection in primary human DCs. DENV replication enhanced autophagosome formation in primary human DCs, and intrinsically-heightened autophagosome biogenesis correlated with relatively higher rates of DC susceptibility to DENV. Furthermore, our data suggest that viral replication intermediates co-localize with autophagosomes, while productive DENV infection introduces a block at the late degradative stages of autophagy in infected DCs but not in uninfected bystander cells. Notably, we identify for the first time that approximately one-fourth of DC-derived CD9/CD81/CD63+ EVs co-express canonical autophagy marker LC3, and demonstrate that DC-derived EV populations are an alternative, cell-free mechanism by which DCs promote DENV transmission to additional target sites. Taken together, our study highlights intersections between autophagy and secretory pathways during viral infection, and puts forward autophagosome accumulation and viral RNA-laden EVs as host determinants of DC-mediated DENV infection in humans. Host-directed therapeutics targeting autophagy and exocytosis pathways thus have potential to enhance DC-driven resistance to DENV acquisition and thereby limit viral dissemination by initial human target cells following mosquito-to-human transmission of DENV.

HAP-PEE: A Danish National Study of Challenges Related to Urinating When Away from Home in Women with Neuromuscular Diseases, Impact on Activity and Participation and Prevalence of Lower Urinary Tract Symptoms.

Little is known about the challenges faced by women with a neuromuscular disease (NMD) when having to go to the toilet in other places than home; a topic that is highly important for participation and bladder health. The aim was to investigate whether women with NMD have problems in going to the toilet when not at home, the problems' impact on their social activities, education, and working life, which strategies they use to manage the problems, and the prevalence of lower urinary tract symptoms (LUTS). A national survey containing questions on type of NMD, mobility, impacts on social activities, education, working life, and bladder health was developed by women with NMD and researchers. LUTS were assessed by the International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Modules (ICIQ-FLUTS). Female patients≥12 years (n = 1617) registered at the Danish National Rehabilitation Centre for Neuromuscular Diseases were invited. 692 women (43% ) accepted the invitation; 21% were non-ambulant. 25% of respondents avoided going to the toilet when not at home. One third of respondents experienced that problems in going to the toilet impacted their social life. 43% of respondents refrained from drinking to avoid voiding when not at home, 61% had a low frequency of urinating, 17% had experienced urinary tract infections, and 35% had experienced urine incontinence. Problems were seldom discussed with professionals, only 5% of participants had been referred to neuro-urological evaluation. The results highlight the difficulties in urinating faced by women with NMD when not at home and how these difficulties impact functioning, participation, and bladder health. The study illustrates a lack of awareness of the problems in the neuro-urological clinic. It is necessary to address this in clinical practice to provide supportive treatment and solutions that will enable participation for women with NMD.∥\keywords \KWDtitle KeywordsNeuromuscular diseases\sep women's health\sep toilet facilities\sep urinary tract infection\sep participation\sep rehabilitation \end contstartabstract.

Investigation of potential effects of quercetin on COVID-19 treatment: a systematic review of randomized controlled trials

Objectives: The COVID-19 pandemic has rapidly become a global health crisis. Currently, there are no proven, reliable, specific treatments for COVID-19. Alongside drug interventions, supportive treatments are implemented during the disease. Quercetin, recognized for its antiviral, anti-inflammatory, anti-aging, and antioxidant properties, is under evaluation in this study for its potential impact on preventing, influencing the course, and mitigating the severity of COVID-19. Methods: A thorough search was conducted across scientific databases, including PubMed, Embase, Web of Science, SAGEpub, Copernicus, Cochrane Library, ScienceDirect, Elsevier, Scopus, Google Scholar, EBSCOhost, Crossref, Ovid-LWW, and DergiPark databases, between 1 November 2021 and 1 April 2022 to ensure a comprehensive inclusion of relevant studies. Results: Thirteen randomized controlled clinical trials (five published, eight unpublished) were identified. Existing literature supports quercetin’s role as a potent free radical scavenger with robust antioxidant properties. It exhibits anti-inflammatory characteristics by inhibiting lipid peroxidation and restraining pro-inflammatory enzymes such as lipoxygenase and phospholipase A2. Scholarly discourse suggests that quercetin supplementation within the 500-1500 mg range leads to favorable outcomes, including quicker patient discharge, reduced inflammation, increased respiratory rate, accelerated viral clearance, and an improved disease prognosis. However, it is noted that intervention durations vary across studies. Conclusions: The analysis of the studies suggested that quercetin is a promising therapeutic agent that can cause a decrease in disease symptoms, frequency of hospitalization, hospital stay, need for non-invasive oxygen treatment, need for intensive care, and mortality. Nonetheless, more clinical studies are needed to better understand quercetin’s curative effects on COVID-19 infection.

Primed IFN-γ-Umbilical Cord Stem Cells Ameliorate Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disorder affecting the temporomandibular joint (TMJ), marked by persistent inflammation and structural damage to the joint. Only symptomatic treatment is available for managing TMJOA. Human umbilical cord mesenchymal stem cells (hUC-MSCs) show potential for treating TMJOA via their immune-modulating actions in the disease area. In addition, stimulation of inflammatory cytokines such as interferon-gamma in hUC-MSCs improves the therapeutic activity of naïve stem cells. Emerging evidence indicates that macrophages play significant roles in regulating joint inflammation through diverse secreted mediators in the pathogenesis of TMJOA. This study was conducted to evaluate the effects of inflammatory cytokine-stimulated hUC-MSCs in repairing TMJOA-induced cartilage lesions and the role of macrophages in the disease. Our in vitro data showed that stimulated hUC-MSCs induce M2 polarization of macrophages and enhance the expression of anti-inflammatory molecules. These effects were subsequently validated invivo. In a rat model of TMJOA, stimulated hUC-MSCs ameliorated inflammation and increased M2 macrophages ratio. Our results indicate that hUC-MSCs stimulated by inflammatory cytokines modulate the activation of M2 macrophages, thereby shifting the local osteoarthritis microenvironment toward a prochondrogenic state and facilitating cartilage repair in inflammatory conditions. Stimulating hUC-MSCs with inflammatory cytokines could potentially offer an effective therapeutic approach for TMJOA, with macrophages playing a pivotal role in immune modulation.

The CHOIR study: acute hemodynamic effects of different pacing strategies in hypertrophic obstructive cardiomyopathy

Abstract Background The majority of patients with hypertrophic cardiomyopathy present with dynamic left ventricular (LV) outflow tract obstruction (LVOTO), referred to as hypertrophic obstructive cardiomyopathy (HOCM). Symptomatic treatment aims at reducing LVOTO with either medical therapy, invasive septal reducing therapies, or pacemaker therapy. There is conflicting evidence regarding the efficacy of pacemaker therapy. The effect of pacing strategies at physical exertion has not been investigated in HOCM. Purpose To identify the optimal pacing strategy for reducing LVOTO without compromising cardiac output at rest and exercise in HOCM. Methods In this ongoing project, we have so far included eight patients with symptomatic HOCM referred to our hospital for alcohol septal ablation (ASA). The day before ASA, we placed temporary pacing leads in the right atrium, the right ventricular (RV) apex and on the LV lateral wall. We also inserted a pulmonary artery catheter and performed per operative echocardiography. All patients had sinus rhythm. Intrinsic rhythm served as baseline and was followed by atrial sensed RV pacing, LV pacing and biventricular (BiV) pacing at rest and during supine cycling. We assessed LVOTO by echocardiography, and cardiac output by the thermodilution method under intrinsic rhythm and all pacing modalities. Results The mean age was 52±15 years, and two of eight patients were female. The mean maximal LV wall thickness was 16±1 mm. The resting LVOTO was 50±23 mmHg. Due to difficulties in placing the LV lead within a reasonable time frame, complete study protocol was not performed in all patients. All eight patients performed RV pace at rest, but only five patients (63 %) were LV and BiV paced at rest. Five patients performed supine cycling but only four patients completed with RV and BiV pacing. The graphs display LVOTO and CO in sinus rhythm and the different pacing maneuvers at rest and during supine cycling. At rest, 6 out of 8 patients (75%) had LVOTO reduction during RV pace, and CO was unchanged. Four of five patients (80%) had LVOTO reduction during BiV and LV pace compared to sinus rhythm, also with unchanged CO. During supine cycling four of five patients (80%) had a reduction of the LVOTO gradient during RV and BiV pacing, without significant CO change. No complications occurred during the interventions. Conclusion In this ongoing study on cardiac pacing in HOCM, RV, LV, and BiV pacing reduced LVOTO while CO remained unchanged at rest and during exercise.

Treatment Discontinuation in Patients with Psoriasis Treated with Biologics: A Retrospective Analysis of German Health Claims Data.

Plaque psoriasis is a common, often debilitating, chronic autoimmune inflammatory skin disease. Moderate-to-severe forms of psoriasis can be treated with biologics such as anti-interleukin and anti-tumor necrosis factor antibodies. We aimed to investigate treatment discontinuation among patients with psoriasis who initiated biologic treatment. We conducted a retrospective, non-interventional cohort study based on anonymized claims data from the German statutory health insurance which covered the years from 2016 to 2021. We included adult patients with psoriasis who initiated biologic treatment in drug-specific cohorts. Over a 365-day follow-up period, we assessed the frequencies and the time until treatment discontinuation for different biologics. Differences in discontinuation rates were compared using a multivariate Cox proportional hazards model. A total of 2565 patients with psoriasis who initiated treatment with secukinumab (n = 612), adalimumab (n = 454), guselkumab (n = 354), ixekizumab (n = 259), ustekinumab (n = 241), tildrakizumab (n = 205), brodalumab (n = 166), risankizumab (n = 145), etanercept (n = 91), certolizumab (n = 29), and infliximab (n = 9) were included. A total of 1290 patients (50.29%) discontinued treatment during the follow-up period, ranging from 30.34% (risankizumab) to 69.23% (etanercept). Median time until discontinuation of treatment ranged from 102days (etanercept) to 208days (risankizumab). Once the biologic treatment was discontinued, 45.05% of patients restarted the treatment with the same agent, 23.10% of patients switched to another biologic, and 31.86% received no further biologic agent. Compared to patients treated with risankizumab, the treatment discontinuation rate was significantly higher (p < 0.05) in patients treated with the other biologics except ustekinumab (p = 0.12). Further research should explore reasons leading to treatment discontinuation in order to support treatment choices for patients with moderate-to-severe psoriasis.

#2358 Impact of COVID-19 on the clinical course of nephrotic syndrome in children: a single-center study

Abstract Background and Aims Children with nephrotic syndrome may experience disease relapse or aggravation triggered by various viral infections. Limited studies on the clinical implications of the coronavirus disease 2019 (COVID-19) pandemic in children with nephrotic syndrome have been published worldwide. Therefore, this study aimed to investigate the effects of COVID-19 on the clinical course of nephrotic syndrome in children. Method The medical records of pediatric patients with idiopathic nephrotic syndrome who visited our hospital between February and June 2022 were retrospectively analyzed. Patients aged &amp;lt;1 year and &amp;gt;19 years and those with inadequate medical records were excluded. Finally, total 59 patients (20 pediatric patients diagnosed with COVID-19 and 39 pediatric patients who did not have COVID-19) were included in the study. Results Twenty of the total 59 patients with nephrotic syndrome were diagnosed with COVID-19 during the study period. The mean age at the time of the diagnosis of nephrotic syndrome and COVID-19 in all 20 patients was 4.6 ± 3.5 and 8.9 ± 3.9 years, respectively. Three patients (15%) were diagnosed with nephrotic syndrome relapse during COVID-19 and the relapse rate was similar to them without COVID-19 (20.5%, 8/39 patients). At the time of the COVID-19 diagnosis, fever (85%) and cough (40%) were the most common symptoms. After the diagnosis of COVID-19, all patients showed improvement with symptomatic treatment, including antipyretic analgesics and cold medicine. None of the critical patients required hospitalization or oral antiviral medications. Conclusion Despite the use of immunosuppressants, the clinical manifestations of COVID-19 in children with nephrotic syndrome were not severe and are expected to be similar to that in the general population. The relapse rate of nephrotic syndrome in children with COVID-19 was also not different from them without COVID-19.

Translational Approach Using Advanced Therapy Medicinal Products for Huntington's Disease.

Current therapeutic approaches for Huntington's disease (HD) focus on symptomatic treatment. Therefore, the unavailability of efficient disease-modifying medicines is a significant challenge. Regarding the molecular etiology, targeting the mutant gene or advanced translational steps could be considered promising strategies. The evidence in gene therapy suggests various molecular techniques, including knocking down mHTT expression using antisense oligonucleotides and small interfering RNAs and gene editing with zinc finger proteins and CRISPR-Cas9-based techniques. Several post-transcriptional and post-translational modifications have also been proposed. However, the efficacy and long-term side effects of these modalities have yet to be verified. Currently, cell therapy can be employed in combination with conventional treatment and could be used for HD in which the structural and functional restoration of degenerated neurons can occur. Several animal models have been established recently to develop cell-based therapies using renewable cell sources such as embryonic stem cells, induced pluripotent stem cells, mesenchymal stromal cells, and neural stem cells. These models face numerous challenges in translation into clinics. Nevertheless, investigations in Advanced Therapy Medicinal Products (ATMPs) open a promising window for HD research and their clinical application. In this study, the ATMPs entry pathway in HD management was highlighted, and their advantages and disadvantages were discussed.

#2699 Rare glomerular microangiopathy: clinicopathological characteristics and prognosis

Abstract Background and Aims Different from the typical histologic changes of thrombotic microangiopathy (TMA), we identified a group of patients whose pathology with glomerular involvement without blood vessel lesions, which was rare and known as glomerular microangiopathy (GMA). Method In Peking Union Medical College Hospital, a total of 33 patients were diagnosed as GMA with proliferation and swelling of glomerular endothelial cells, fragmented red blood cells, fibrin or platelet thrombi in the capillary lumen, thickening of the basement membrane, stenosis or occlusion of capillary lumen, but no abnormalities in the endothelium of renal small vessels. The pathology and clinical data were from the medical records and analyzed. Results The patients were 66.7% male with a mean of 45 years (14 to 74 years). The primary diseases were Castleman's disease (CD, 30.3%), POEMS syndrome (21.2%), cancer patients receiving agents targeting vascular endothelial growth factor (21.2%), and others. All the patients showed various degrees of proteinuria, with an average 24-hour urinary protein of 2.66 g/d, hematuria (63.6%), and acute kidney injury (AKI, 39.4%). The median serum creatinine (SCr) was 142 (107.5, 169) μmol/L. The AKI patients had lower Alb (P &amp;lt; 0.0001), PLT (P = 0.0192), higher high-sensitivity C-reactive protein (hs-CRP) (P = 0.0199), and reduction of IgA (P = 0.0021). There is no significant difference in SCr and proteinuria among patients with different etiologies. The CD patients exhibited higher hs-CRP and D-Dimer. Treatment included targeting therapy of underlying hematological disorders, glucocorticoid combination with or without immunosuppressant, and supportive treatment. After treatment, we observed proteinuria remission (66.7%), partial improvement (27.3%), or complete recovery (45.5%) of renal function. Conclusion In Castleman's disease, POEMS syndrome, and patients receiving agents targeting VEGF, initial attention to GMA might improve the prognosis and shed light on the study of the mechanisms.

#1170 Efficacy and safety of telitacicept in IgA nephropathy: a real-world study

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerular disease in the world, and the specific therapeutic methods are limited in IgAN. Telitacicept is a humanized fusion protein composed of a transmembrane activator and calcium-modulating cyclophilin ligand interactor receptor and human IgG. This study was designed to evaluate the efficacy and safety of telitacicept in adult patients with IgAN in a real-world study. Method Biopsy-proven IgAN patients with 24-hour proteinuria greater than 0.5 g/day who received telitacicept 240 mg once a week were recruited in this study and 1:1 matched with patients who received supportive treatment only or immunosuppressive treatment by propensity score matching. The primary outcome was the change from baseline in 24-hour proteinuria over the 3-month follow-up. Results Twenty-one patients in each group were enrolled. The mean eGFR was 80.1 ml/min/1.73 m2, and the median 24-hour urine protein level was 1.48 g/day. At the end of the 3-month follow-up period, telitacicept reduced median proteinuria by 0.72 g/d (54.6%) from baseline, compared with a reduction of 0.18 g/d (20%) in the supportive treatment group (P &amp;lt; 0.001), and 1.12 g/d (72.1%) in the immunosuppressive treatment group (P = 0.814). Preserved eGFR levels were observed in the telitacicept group (1.9 ml/min/1.73 m2 [4.3%]), while the eGFR level declined in the supportive treatment group (- 2.9 ml/min/1.73 m2 [- 5.8%]) and immunosuppression group (- 6.1 ml/min/1.73 m2 [- 8.4%]). No serious adverse events were observed in the telitacicept treatment group. Injection site reactions were more prevalent in the telitacicept group (8/21 [38.1%]), meanwhile immunosuppression group had more respiratory tract infections (7/21, [33.3%]). Conclusion Telitacicept can reduce proteinuria in patients with IgAN and showed a favourable safety profile in patients with IgAN.

Safety and Effectiveness of Liv.52 DS in Patients With Varied Hepatic Disorders: An Open-Label, Multi-centre, Phase IV Study.

Background The hepatoprotective function of polyherbal formulation Liv.52 in chronic liver diseases is well recognized in published literature. The objective of this open-label, phase IV study was to further strengthen and validate its safety and effectiveness using a large patient pool in a real-world scenario and provide scientific data on symptomatic improvement and supportive treatment in liver function with improvement in quality of life. Methods Adult patients of either sex with one or more clinical symptoms like fatigue, nausea, anorexia, abdominal pain or discomfort, muscle cramps, jaundice, or any other signs and symptoms with a history suggestive of mild-to-moderate hepatic disorders like alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), drug-induced hepatotoxicity, or hepatitis were treated with two Liv.52 DS tablets (oral) twice daily for 12 weeks. Results Out of the 1000 enrolled patients, 962 (96%) completed the study with the following subgroups ALD: 375 (38.9%), NAFLD: 379 (39.3%), drug-induced hepatotoxicity: 78 (8.1%), hepatitis: 130 (13.5%). The mean age of enrolled patients was 37.7 years, and the majority of them, 785 (78.5%) were men. The common adverse events observed (with >1.5% incidence) in the study were abdominal pain: 26 (2.6%) and headache: 17 (1.7%). Liv.52 showed statistically significant improvement (P<0.0001) in various clinical signs and symptoms in the majority of patients namely, fatigue: 357/723 (49%), anorexia: 485/620 (78.2%), jaundice: 48/52 (92%). Majority of the patients showed significant improvements from baseline to end of 12 weeks in the liver function test parameters namely, aspartate aminotransferase: 633/840 (75.36%), alanine aminotransferase: 592/729 (81.21%), serum bilirubin: 244/347 (70.32%), alkaline phosphatase: 279/355 (78.59%) with P<0.0001 for all parameters. Statistically significant improvement (P<0.005) was also seen in all the components of the chronic liver disease questionnaire (CLDQ) scores from baseline to 12 weeks. Conclusions The study demonstrated that Liv.52 was hepatoprotective and well tolerated in the study population after treatment for 12 weeks. Significant improvements were seen in clinical signs and symptoms, laboratory parameters of liver function, and CLDQ scores from baseline to 12 weeks. No significant or new safety signals emerged from this study.

#1728 New onset proteinuria in two pregnancies: glomerulopathy or preeclampsia?

Abstract Background and Aims Distinguishing between preeclampsia in pregnant women and a new onset glomerulonephritis could be challenging. Method Here, we present two cases on new onset proteinuria during pregnancy which were diagnosed with primary membranous nephropathy and their treatment. Results Case 1. A 27-year-old patient, G6P5A1, was referred to our attention at the 14th week of gestation (wg) for new onset proteinuria of about 5 g/day. She had a personal history of preeclampsia and was already under low-dose Aspirin since the beginning of this pregnancy. She was normotensive, her serum albumin was about 1.8 g/dl (Fig. 1A) and showed no edema. Due to the timing of pregnancy, a glomerular disease was suspected, and she was started on oral prednisolone 20 mg/day. Complementary explorations found a normal SFlT-1 to PlGF ratio as well as normal renal function and positive anti-PLA2R antibodies. A diagnosis of membranous nephropathy diagnosis was, therefore, made. Cyclosporine (CsA) 300 mg twice daily was started, prednisolone was rapidly tapered, and partial remission was rapidly attained. The rest of her pregnancy was uneventful until the 36 wg when hypertension, increase in proteinuria and findings of IUGR developed; on the account of the diagnosis of superimposed preeclampsia, delivery was decided (caesarian section) giving birth to a healthy female baby weighting 1.9 kg (1st Intergrowth centile). After the delivery the patient underwent two injection of Rituximab (Rtx) (1 g 2 weeks apart) and CsA was discontinued. The patient achieved partial remission, and her antibody titer decreased but remained positive. A renal biopsy is scheduled to guide future treatment options. Case 2. A 44-year-old patient, G3P2A1, without history of previous preeclampsia, was referred to our attention at 32 wg for new onset proteinuria around 5 g/day first discovered at 10 wg. Her blood pressure was normal. She was already under Aspirin treatment, based on a suspicion of preeclampsia, which was however ruled out by the timing of proteinuria onset. At referral additional investigations revealed an increase in proteinuria up to 19 g/l, normal renal function, gestational diabetes, normal SFlT-1 to PlGF ratio and a serum albumin around 1.4 g/dl (Fig. 1B). Anti-PLA2R antibodies were positive, and a membranous nephropathy was diagnosed at 34 wg. Immunosuppression treatment was waived considering the timing of pregnancy and supportive treatment by LMW heparin was started. The patient delivered at 37 wg by urgent cesarian section on the account of onset of hypertension, giving birth to a male baby weighting 2760 g (37th Intergrowth centile). CsA treatment was started 5 days after delivery and Rtx infusion followed 2 weeks after delivery, on the account of her decision to breastfeed. CsA was discontinued 2 months after Rtx first injection with complete sustained remission and undetectable PLA2R antibodies. Conclusion Preeclampsia is the most frequent complication of pregnancy. In particular before the 20 wg the distinction between an hypertensive disorder of pregnancy (HDP) and primary glomerular disease is fundamental but may be difficult. In our cases, the early onset of proteinuria was in favor of a primitive disease of the kidney. Complementary explorations allowed diagnosing membranous nephropathy. The treatment of glomerulonephritides, either of new onset or chronic, during pregnancy is challenging. Renal biopsy has a higher risk of complications, especially in mid-pregnancy, and finding positive anti PLA2R antibodies may allow avoiding the histological examination. It is worth noting that preeclampsia developed in both cases towards the end of gestation, stressing the role of chronic kidney disease as a major risk factor for HDP. The SFlT-1 to PlGF ratio could come in handy both for differential diagnosis and for diagnosis of superimposed preeclampsia.

A review of treatment of relapsing-remitting type of multiple sclerosis (RRMS)

Introduction Multiple sclerosis (SM) is the most common chronic inflammatory-demyelinating disease of the Central Nervous System. In its course, a multifocal damage is done to a nervous tissue - myelin sheaths surrounding axons become disintegrated. This process leads to a dysfunction of the electrical impulses passage along nerve fibers which occurs as various symptoms that hinder the functioning of the patients. Aim of the study This review aims to summarize treatment methods of relapsing-remitting type of multiple sclerosis (RRMS). Following information will be presented: groups of medications, mechanism of its action, its most important side effects and its effectiveness. Material and method This review presents the current state of knowledge about relapsing-remitting type of multiple sclerosis (RRMS) treatment - it is based on Pubmed database and was carried out using keywords concerning the issues of multiple sclerosis. Cited articles were selected in order to base on up-to-date investigation results. Summary A wide range of therapeutic options let neurologists treat their patients accurately, but the basic knowledge about each substance should be assimilated to choose the best individual therapy. Patients suffering from multiple sclerosis differ from each other and a personal approach is needed to implement appropriate treatment as soon as possible. Early start allows patients to not to lose their everyday functioning areas, as the neurodegenerative process is stopped at the initial stage. If some changes in brain tissue structure are permanently done, neurologists should know the options of symptomatic treatment to alleviate a patient's suffering.

#992 Protocol based on PLA2R1 epitope recognition is superior to standard protocol in achieving remission in PLA2R1-associated membranous nephropathy

Abstract Background and Aims Membranous nephropathy (MN) is a rare, but severe autoimmune disease affecting kidney glomeruli. Clinical evolution is variable, ranging from spontaneous remission to persistent nephrotic syndrome and kidney failure. The major autoantigen in MN is PLA2R1 protein associated with 50-70% of all cases. Patients may present antibodies against a single immunodominant CysR domain or may develop additional antibodies against CTLD1 and/or CTLD7 and/or CTLD8 domains of PLA2R1 defining a cascade immunization or epitope spreading. The mechanism of epitope spreading has been described in a variety of contexts: it can reinforce immune response to eliminate a pathogen, but can also be associated with the aggravation of autoantibody-mediated autoimmune pathologies. The value of this marker in the management of MN patients remains debated. Our initial study (confirmed on an independent cohort) has shown that the single domain recognition (non-spreader patients) is associated with a higher chance of spontaneous remission (45% vs 0.05% in GEMRITUX cohort) and a better response to treatment (100% of remission regardless of the dose of rituximab used). The patients with multi domain recognition (spreader patients) of CTLD1 and/or CTLD7 domains, on the other hand, have poor prognosis and are less likely to achieve remission requiring high doses of rituximab. Based on these studies we have proposed a personalized treatment protocol with either low or high dose Rituximab based on patients’ PLA2R1 epitope spreading status. The aim of this study was to evaluate the efficacy of this personalized treatment in comparison to the established GEMRITUX protocol. Method A multicenter, randomized, controlled, prospective clinical trial was conducted in 12 French hospitals. Sixty-four consecutive patients with PLA2R1-related MN were randomly assigned to either the control group following the GEMRITUX protocol (symptomatic treatment for 6 months, two 375 mg/m2 rituximab infusions at month-6 in case of persistent nephrotic syndrome (NS)) or the personalized treatment (PMMN) group (patients with no epitope spreading at month-0 were treated as per GEMRITUX protocol, while patients with epitope spreading at month-0 or month-6 with persistent NS were treated immediately with two 1 g rituximab infusions). The primary study outcome was the rate of clinical remission at month-12. The secondary outcomes were complete and partial remission, immunological remission, proteinuria, albuminuria, serum creatinine, and PLA2R1 antibody titer. Results From 64 patients included, three were excluded from final analyses due to loss to follow-up. There was no difference in age, gender, albumin, UPCR, anti-PLA2R1 titer and the rate of PLA2R1 epitope spreading at baseline between the two groups. At M12, 34% of patients from the GEMRITUX group and 69% of patients from PMMN group achieved partial clinical remission (P = .0105) defined as UPCR &amp;lt; 3.5 g/g with a decrease greater than 50% from baseline; improvement or normalization of serum albumin; and increase of serum creatinine lower than 20%. While there was no difference in remission rate between the GEMRITUX group and PMMN group for patients with single domain recognition (38% vs 50%, respectively, P = .7107), multi-domain recognizers (spreaders) were more likely to achieve remission with personalized protocol (36% vs. 87%, P = .0078). The rate of complete clinical remission between the two experimental groups, defined as UPCR &amp;lt;0.3 g/g and normal albumin, was close to statistical significance (0% vs 16%, P = .0538). Conclusion Personalized treatment protocol based on the stratification of patients with PLA2R1-related MN according to their epitope spreading status, is superior to the standard GEMRITUX protocol in achieving partial clinical remission at 12 months. Patients with multiple domain recognition should be treated immediately with high doses of rituximab to increase their chances of remission.

#1165 Targeted-release budesonide can preserve the glomerular filtration rate in patients diagnosed with IgA nephropathy after 3 months of administration.

Abstract Background and Aims The four-hit hypothesis constitutes the main immunological sequence of the IgA nephropathy (IgAN) pathogenesis. However, the activation of intestinal-renal axis is considered the initial step during IgA nephropathy (IgAN) pathogenesis. Aim of this prospective pilot study is to evaluate parameters which influence early response to targeted release budesonide. Method Adult IgAN patients, diagnosed the last 10 years, maintaining eGFR &amp;gt;30 ml/min/1.73m2 and Uprotein &amp;gt;750 mg/24 hr, despite standard supportive treatment, commenced on budesonide 16 mg/d, and followed for 3 months. Renal biopsies were re-evaluated and scored according to Oxford classification, parameters of renal function recorded at time of diagnosis (T-d),at the beginning of treatment (T0), and 3 months later (T3). Results Fifteen IgAN patients, M/F:12/3, Mean age: 52 (34-74) years from two different departments fulfilled the criteria and they have already started on budesonide treatment, 51.6 ± 45 months following diagnosis. eGFR had declined from T-d to T0, 57.43 ± 10.58 to 49.23 ± 13.63 ml/min/1.73 m2, p = 0.03, and Uprot was stable 3.33 ± 1.16 to Uprot = 2.98 ± 1.19 gr/24 hrs, p = NS. During the 3 first months of budesonide (T3), eGFR showed slight improvement, eGFR = 54.38 ± 13.67 while Uprot remained stable 3.17 ± 1,04 gr/24 hrs. Improvement in renal function was not associated with any of histologic findings, but was remarkably more evident within patients with &amp;lt;4 years of diagnosis, eGFR from 62 ± 5.2 to 73 ± 2.4, compared to change in the eGFR from 23 ± 5.6 ml/min/1.73 m2 to 25 ± 3.6 ml/min/1.73 m2. Conclusion Our preliminary findings suggest that, independent of renal histology, budesonide treatment showed a trend in improving renal function, mainly in patients with relatively short time from diagnosis. So, budesonide can

Role Of Acute Vascular Distress Syndrome In The Development Of Multisystem Inflammatory Syndrome In Sars-Cov-2 And Modern Views On The Research And Treatment Of Critical Coronavirus

Background: The COVID-19 pandemic, caused by SARS-CoV-2, has highlighted the complex pathology of the virus, which extends beyond respiratory symptoms to include multisystem inflammatory syndrome (MIS). This review explores the role of Acute Vascular Distress Syndrome (AVDS) in the development of MIS in both adults (MIS-A) and children (MIS-C), providing a comprehensive overview of modern research and treatment approaches for severe coronavirus infections. Methods and Materials: This review synthesizes findings from multiple studies and clinical reports to analyze the mechanisms by which SARS-CoV-2 induces AVDS and subsequently MIS. Key materials include molecular and cellular research data, clinical case studies, and treatment protocols. Diagnostic tools such as PCR and serological testing, as well as various biomarkers like neurofilament light chain and galectin-3, are discussed to elucidate their roles in identifying and managing severe COVID-19 cases. Results: The interaction between SARS-CoV-2 and host endothelial cells, mediated by ACE2 receptors, triggers a cascade of inflammatory responses leading to AVDS. This syndrome is characterized by severe endothelial dysfunction, cytokine storms, and mitochondrial distress, which collectively contribute to the pathogenesis of MIS. Clinical evidence indicates that AVDS is a critical factor in the severity of COVID-19, with widespread implications for multiple organ systems, including the central and peripheral nervous systems. Conclusion: Understanding the role of AVDS in MIS development offers valuable insights into the pathophysiology of severe COVID-19. Effective management requires a multifaceted approach, combining antiviral therapies, immunomodulators, and supportive treatments like extracorporeal membrane oxygenation (ECMO). Future research should focus on targeted therapies to mitigate endothelial damage and improve patient outcomes in critical COVID-19 cases.

A rare case of polyarthritis panniculitis and pancreatitis.

Extra pancreatic manifestations of pancreatitis are rare, with a prevalence of 2-3%. One such rare manifestation is the triad of joint pain (polyarthritis), tender skin lesions (panniculitis), and pancreatic inflammation (pancreatitis), known as PPP. The pathogenesis of this phenomenon is not fully understood but is believed to involve lipolysis by pancreatic enzymes at lipid-rich skin and joint sites. PPP primarily affects middle-aged males with a history of alcohol use disorder. Diagnosis can be challenging due to the absence of typical abdominal symptoms. Delayed diagnosis may significantly worsen outcomes. Supportive therapy is the mainstay, but resolution requires addressing the underlying pancreatic abnormality. We present a case of a patient with a history of alcohol use disorder and recurrent acute pancreatitis who developed joint pain and skin rash. Extensive work-up ruled out other causes, and imaging and biopsy confirmed the diagnosis of PPP. Symptomatic management and treatment of the underlying pancreatic abnormality led to complete resolution of symptoms. Our case serves to raise awareness of this rare but potentially fatal syndrome.

Hyperbaric oxygen therapy improves the efficacy of conventional supportive treatment for late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation

ABSTRACT Objective This study aims to investigate the efficacy and safety of hyperbaric oxygen therapy (HBOT) in the treatment of late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Methods This retrospective analysis included 16 patients with late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation between 2016 and 2022. Among them, 8 patients received HBOT in addition to conventional treatment, while the other 8 received only conventional treatment. The clinical efficacy and safety of HBOT were evaluated by comparing the Numeric Rating Scale pain scores and clinical grades of hematuria before and after treatment, reflecting the patients’ urinary pain and hematuria status. Results The patients were divided into two groups based on whether they received HBOT. The group that received HBOT (n = 8) had a shorter duration of illness compared to the non-HBOT group (n = 8) (p < 0.05). The time for the NRS to decrease to below 2 was also shorter in the HBOT group. Furthermore, the patients who received HBOT did not experience any significant adverse reactions. Conclusion The combination of conventional treatment and hyperbaric oxygen therapy (HBOT) has been shown to improve symptoms such as urinary pain, frequency, urgency, and hematuria in patients with late-onset hemorrhagic cystitis after transplantation. This approach has been proven to be safe and effective.

Drug-related exanthema under immunotherapy and targeted oncological therapy

Oncological therapies can cause avariety of mucocutaneous adverse events. Exanthematous adverse events can be challenging in the context of the urgent need for cancer treatment due to their spread, sometimes rapid progression, and mucous membrane or organ involvement. This article provides an overview of the most important exanthematic dermatoses as side effects of modern drug-based tumor therapies with diagnostic and therapeutic information for clinicians, taking into account the current literature and guidelines. Exanthematous adverse events of immune checkpoint inhibitors, EGFR antagonists, kinase inhibitors, bispecific T‑cell engagers, and the CCR4 inhibitor mogamulizumab are reviewed in detail. Cutaneous side effects are common across all drug classes and cover abroad spectrum. While some adverse events are specific to one drug class, many exanthemas can occur with both oncological immunotherapies and various targeted therapies. Areliable diagnosis, dose adjustment or discontinuation of the offending agent in consultation with the treating oncologists and appropriate symptomatic therapy are important for correct management. In the case of severe, life-threatening drug reactions, however, permanent discontinuation of the drug is essential.

Predictors of Fatal Outcome in Newly Diagnosed Tuberculosis/HIV Co-Infection with Chronic Alcoholism (Clinical Case)

Our own case of tuberculosis/HIV co-infection’s diagnosis in chronic alcoholism and analysis of the fatal outcome predictors are presented. The patient abused alcohol for a long time in the presented case, he was hospitalised with acute psychosis in a psychoneurological dispensary, where pulmonary tuberculosis and HIV infection were diagnosed for the first time during additional examination. The patient was admitted to the department in serious condition after prolonged alcohol intoxication. The patient’s condition stabilized after detoxification therapy. Antimycobacterial therapy according to the scheme of an individual treatment regimen, antiretroviral therapy, treatment of hepatitis B and C, detoxification therapy, prophylaxis with Biseptol and Fluconazole and symptomatic therapy were prescribed. After 20 days immune reconstitution inflammatory syndrome developed. It was manifested with meningitis and cryptococci were detected in the cerebrospinal fluid 17 days later. Prescribed treatment of cryptococcal meningoencephalitis with fluconazole in high doses intravenously had a significant positive effect, which made it possible to reduce the dose of the drug to the maintenance level. The treatment was not stopped, but sterility of the liquor was not achieved. After 98 days the patient entered a coma and after 113 days he died from the progression of multiple organ failure and cryptococcal meningitis. It should be noted that the patient was diagnosed with tuberculosis with multiple drug resistance for the first time, the treatment of which had positive dynamics, despite the progression of multiple organ failure and the presence of cryptococcal meningoencephalitis. Therefore, although tuberculosis was not the direct cause of the patient’s death, the disease itself deepened the severity of the general condition. Considering the presented clinical case, it was established that predictors of the fatal outcome of newly diagnosed tuberculosis/HIV co-infection in chronic alcoholism are: antisocial lifestyle; concomitant diseases (tuberculosis, chronic viral hepatitis B and C); cryptococcal meningoencephalitis; fever, altered mental status, cryptococci in the cerebrospinal fluid; the number of CD4+ lymphocytes is less than 200/μL; lack of early screening for CrAg; early initiation of antiretroviral therapy before the diagnosis of cryptococcal meningoencephalitis, which provokes immune reconstitution inflammatory syndrome, against the background of which cryptococcal infection progresses; monotherapy of cryptococcal meningoencephalitis with Fluconazole. Knowledge and practice gaps among medical practitioners contribute to the high fatality rate of cryptococcal meningoencephalitis in tuberculosis/HIV co-infection in chronic alcoholism.