Severe Relapse Research Articles

Immunohistochemical staining seems mandatory for individualizing and shortening follow-up in unilateral primary aldosteronism.

The clinical significance of immunohistochemistry (IHC) for unilateral primary aldosteronism (PA) has been unclear. Individualized follow-up of PA patients could be in sight. Long-term outcomes of patients, classified based on IHC, need further investigation. We aimed to assess long-term clinical outcomes for unilateral PA, classifying patients based on IHC. A nationwide observational study, with up to 16 years follow-up, executed in 2007-2016 at Landspitali University Hospital, tertiary referral center. Patients were diagnosed and treated in line with the current guidelines. Haematoxylin and eosin (H&E) tissue slides were stained using CYP11B1 and -B2 antibodies. All cases were re-evaluated and classified according to the HISTALDO consensus. Outcomes were assessed using the PASO criteria. All unilateral PA patients diagnosed in 2007-2016 in Iceland, 26 patients aged 28-73 years, who underwent adrenalectomy, were included. Aldosterone, renin, and cortisol values, use and dosage of antihypertensives, potassium supplementation, blood pressure and serum potassium pre-intervention and throughout follow-up, and histopathology results post-adrenalectomy. Following IHC, an aldosterone-producing nodule was seen in 12 adrenals, an aldosterone-producing adenoma in 10 and multiple aldosterone-producing micronodules in four. IHC altered histopathology from previous H&E diagnosis in 23% (6/26) of the patients. In total, 81% (21/26) of the patients had partial clinical success. Eight percent (2/26) of the patients needed potassium supplementation during follow-up. In the classical group, the AVS results were more determinative with significantly higher lateralization index (median 10.1 vs. 5.3, p = .04) and more contralateral suppression (median nondominant ratio 0.4 vs. 1.0, p = .03). One out of five patients with complete clinical success at 12 months post-op had severe relapse later, the other four were normotensive without antihypertensives for up to 10 years. We found IHC mandatory for accurate histopathologic diagnosis of PA. Our results support the importance of contralateral suppression when interpreting AVS results. Also, the study highlights the complicated assessment of clinical outcome and importance of aldosterone and renin measurements during follow-up.

Integrating an addiction team into the management of patients transplanted for alcohol-associated liver disease reduces the risk of severe relapse

Background & AimsLiver transplantation (LT) is a last resort treatment for patients at high risk of mortality from end-stage liver disease. Over the past years, alcohol-associated liver disease has become the most frequent indication for LT in the world. The outcomes of LT for alcohol-associated liver disease are good, but return to alcohol use is detrimental for medium-term survival because of cancer development, cardiovascular events, and recurrent alcohol-associated cirrhosis. Several strategies have been developed to prevent return to alcohol use during the pre- or post-LT period, but there are no specific recommendations. Therefore, the main objective of this study was to investigate if the integration of an addiction team in a LT unit affected the rate of severe alcohol relapse after LT. The secondary objectives were to assess the effects of addiction follow up on cardiovascular events, cancer, and overall survival. MethodsThis study was a retrospective comparison between centres with or without addiction monitoring. ResultsThe study included 611 patients of which 79.4% were male with a mean age of 55.4 years at the time of LT, 190 were managed by an integrated addiction team. The overall alcohol relapse rate was 28.9% and the rate of severe relapse was 13.0%. Patients with addiction follow-up had significantly less frequent severe alcohol relapse than those in the control group (p = 0.0218). Addiction follow up (odds ratio = 0.19; p = 0.001) and age at LT (odds ratio = 1.23; p = 0.02) remained significantly associated with post-LT cardiovascular events. ConclusionsOur study confirms the benefits of integrating an addiction team to reduce return to alcohol use after LT. Clinical Trials registrationThis study is registered at ClinicalTrials.gov (NCT 04964687). Impact and implicationsThe main indication for liver transplantation is alcohol-associated cirrhosis. There are currently no specific recommendations on the addiction monitoring of transplant candidates, although severe return to alcohol use after liver transplantation has a negative impact on long-term survival of patients. In this study, we explored the impact of a systematic addiction intervention on the return to alcohol use rates. In our transplantation centre, we demonstrated the interest of an addiction follow up to limit the severe alcohol relapses rate. This information should be further investigated in prospective studies to validate these data.

Comparative analysis of the course of COVID-19 and post-COVID syndrome in patients with inflammatory bowel disease and COVID-19 caused by the Omicron strain and earlier strains

BACKGROUND: Patients with inflammatory bowel disease have specific features of the course of COVID-19 and post-COVID syndrome. The available literature is limited in data comparing the course of COVID-19 of different strains in patients with inflammatory bowel disease as well as assessing the course of post-COVID syndrome.
 AIM: To conduct a comparative analysis of the course of COVID-19 and post-covid syndrome in patients with inflammatory bowel disease and COVID-19 caused by the Omicron strain and earlier strains.
 MATERIALS AND METHODS: The study included 159 patients diagnosed with ulcerative colitis and Crohns disease and COVID-19, who were observed in two temporary infectious diseases hospitals in Kazan (Republican Clinical Hospital and City Clinical Hospital No. 7) and on outpatient basis since April 2020 to May 2022. For a comparative analysis of the course of COVID-19 and post-COVID syndrome in patients who had come through COVID-19, 2 periods were defined: the 1st period from March 2020 to December 2021, the 2nd period from January 2022.
 RESULTS: None of the patients with Omicron developed lung damage (0 (0%) vs 36 (44.4%), p 0.05). It has been also found that among patients with Omicron there were more patients with comorbidity (62 (79.5%) versus 50 (61.7%), (p 0.05).
 Dynamic observation of the patients has revealed that post-covid syndrome was significantly less common in the patients with Omicron for 3 months after COVID-19 (25.6% vs. 47.1%).
 When analyzing the complaints associated with asthenia, it was found that they were significantly more common in the patients with Omicron 3 months after COVID-19 (58 (74.3%) in comparison with 17 (50%), p 0.05). The complaints associated with cognitive impairment (0 (0%) vs. 3 (8.8%), p 0.05) and depression (Hospital Anxiety and Depression Scale (31 (39.7%) vs. 22 (64.7%), p 0.05), Hamilton scale (22 (28.2%) vs. 22 (64.7%), p 0.05)) were significantly less common in the patients with Omicron for 3 months after COVID-19.
 After analyzing the activity in the patients with inflammatory bowel disease before COVID-19 and 3, 6, 9 months after COVID-19, we have found that the maximum number of patients with the exacerbation of inflammatory bowel disease was noted after 3 months in the patients with Omicron and after 6 months in the patients with earlier strains.
 CONCLUSIONS: Thus, the results of the study have shown that in the patients with inflammatory bowel disease, both in ulcerative colitis and Crohns disease, the course of COVID-19 caused by the Omicron strain proceeded in a milder form compared with the patients who had earlier strains. In the patients with Omicron, complaints characteristic of post-COVID syndrome were less common. After a previous infection with COVID-19, the frequency of inflammatory bowel disease relapses increased: in the patients with Omicron due to mild exacerbation 3 months after COVID-19; in the patients with earlier strains due to moderate and severe relapse.

Severe CNS relapse of partially-treated listeria: Hydrocephalus, Brain Oedema, and Coma.

Severe CNS relapse of partially-treated listeria: Hydrocephalus, Brain Oedema, and Coma.

#5091 RITUXIMAB IN MANAGEMENT OF RELAPSING AND STEROID DEPENDANT C1Q NEPHROPATHY: A TALE OF THREE PATIENTS

Abstract Background and Aims C1q nephropathy is an immune glomerular disease in which dominant C1q electron-dense deposits are identified in the mesangium.It commonly presents with nephrotic syndrome, while nephritic syndrome or isolated haematuria are less common. Biopsy findings vary, from no glomerular lesion identified as in minimal change disease (MCD) to focal segmental glomerulosclerosis (FSGS) and immune-mediated proliferative glomerulonephritis. Steroids are the mainstay and other agents have been tried. Rituximab is an anti-CD 20 human/mouse chimeric monoclonal antibody and one of the drugs used in managing C1q nephropathy. We present 3 cases of biopsy-proven C1q nephropathy that presented with nephrotic syndrome. They responded initially to steroids and achieved remission after treatment with rituximab. Method Case Scenarios: Case (1): A 30-year-old man had been diagnosed with steroid sensitive nephrotic syndrome since he was 18 months. Renal biopsy confirmed the diagnosis of C1q nephropathy, more in the spectrum of MCD. He was managed with steroids, and rituximab in 2011 and achieved remission for the last 7 years after 5 doses. His renal function had always remained normal. He presented to our department in 2020 with another relapse and heavy proteinuria (urine protein creatinine ratio (UPCR) was 1300 mg/mmol) but unchanged renal function. Repeat kidney biopsy showed C1q nephropathy in the spectrum of FSGS. He showed good response to oral steroids. On relapse while weaning steroids, Rituximab was considered. He had 2 doses of rituximab of 1 gram 2 weeks apart in July 2021. He achieved full remission over the last 2 years. Case (2): A 77-year-old female presented in 2020 with nephrotic syndrome (UPCR of 660 mg/mmol) and acute kidney injury (AKI) (creatinine 400 μmol/l). Her kidney biopsy showed C1q nephropathy with FSGS features. She was started on haemodialysis due continuous kidney function deterioration. She recovered on steroid therapy to normal kidney function and negative proteinuria, but she relapsed with weaning steroids. So steroid dose was increased and tacrolimus was added. Her renal function remained intact. Following that she had another flare in May 2021 with mild kidney impairment and worse proteinuria (UPCR 500 mg/mmol) while she was on small dose steroid and tacrolimus. She was then started on rituximab. After 2 doses 1 gm 2 weeks apart she achieved remission and her kidney function normalised. She received 2 more doses of 1 gram rituximab 6 months apart with excellent response. She has been in complete remission since. Case (3): A 28-year-old male presented to our department in July 2020 with nephrotic syndrome (urine PCR >900 mg/mmol) and preserved renal function. His kidney biopsy was initially reported as MCD and he was managed with oral steroids. He showed a good response with complete resolution of his proteinuria 3 weeks later and remained in remission for 2 years. However, in August 2022- he suffered a second severe relapse (UPCR 4000 mg/mmol) with preserved renal function. His kidney biopsy was therefore rereviewed and immunofluorescence was added which revealed C1q nephropathy. He had another course of steroids and was initiated on rituximab infusions. He showed full remission after 2 doses (1 gram IV 2 weeks apart) and is on ongoing 6 monthly infusions. Results Rituximab was effective in inducing remission in our patients with nephrotic syndrome due to C1q nephropathy. They were all steroid sensitive. It was effective in both steroid-sensitive and steroid-dependent cases. The first and second cases had biopsy findings in the spectrum of FSGS while the third case histological picture in the spectrum of MCD. They all achieved full resolution of their proteinuria and preserved their renal function finally. Conclusion Rituximab was effective in inducing remission in both steroid-responsive and steroid dependant relapsed patients with C1q nephropathy, despite differences in biopsy results. Kidney function was preserved. More solidified data, including multi-centre randomized controlled trials, are needed to establish clear guidelines for the position of rituximab in the management of the disease and the proper dose to use.

#3849 PERITONEAL DIALYSIS CATHETER LOCK: PREVENTING RELAPSES

Abstract Background and Aims The incidence of peritonitis has markedly decreased in the last decades, nevertheless it remains one of the main causes of catheter removal and subsequent dialysis modality change. In the long-term severe peritonitis and relapses can lead to peritoneal membrane failure. Some bacteria can form biofilms in the peritoneal catheter lumen granting them resistance against antibiotics and thus being one of the causes for infection recurrences. To find a viable way to avoid or/and eradicate the bacterial biofilm in the peritoneal catheters given the importance of infections. Method We present the experience in our peritoneal dialysis unit in the coadjuvant treatment of peritoneal dialysis-associated peritonitis with peritoneal catheter locks in the past few years. We used two kinds of peritoneal catheter lock depending on the isolated germ and divided them in two groups. Group I for the gram-positive staphylococcus group and Group II for gram-negative germs, specifically pseudomona. We reported 12 cases from which 10 were the first episode of gram-positive staphylococcus (epidermidis and Aureus) peritonitis. For the treatment we locked the catheter with 350mg of daptomycin in 7ml of saline solution once a week without using the catheter for 12 hours. For the other 2 cases of pseudomona peritonitis we locked the catheter with taurolidine/urokinase during the exchange with icodextrin twice a week with a 12 hours dwell time until 9 locks were archived. Results We treated 12 patients (Table 1). Peritonitis was resolved without recurrences in 9 of 10 patients in group I. In one case were a Methicillin-resistant Staphylococcus aureus was involved there was no response to the treatment and the peritoneal catheter was removed. In Group II both patients resolved their peritoneal infection without recurrences. Conclusion In our study peritoneal catheter locking seems to avoid the biofilm and reduce the peritoneal infection recurrences.

Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation

Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. Dimethyl fumarate, fingolimod, and ocrelizumab. Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

Effectiveness of rituximab versus oral immunosuppressive therapies in neuromyelitis optica spectrum disorder in a racially diverse cohort of subjects: A single-center retrospective study.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune, inflammatory disorder characterized by severe relapses and high level of disability. In clinical trials of NMOSD, Black patients are under-represented, < 12%, compared to a relatively high prevalence of NMSOD in this population, 10/100,000. Despite the higher prevalence of NMOSD in Black and Asian patients, there is limited knowledge of the effectiveness of disease modifying treatments across racially diverse groups. To assess the effectiveness of rituximab and oral immunosuppressive agents in a cohort of NMOSD patients, the majority of whom are Black, in a real-world, clinical setting. A single-center retrospective study was conducted at the University of Chicago Medical Center. (1) diagnosis according to the 2015 International Panel for NMO Diagnosis (IPND) Criteria, (2) positive anti-aquaporin-4 antibodies on ELISA or cell-based tests, (3) initiation of immunosuppressant therapy within 5 years of disease onset, (4) first-line treatment with rituximab, mycophenolate (MMF), or azathioprine (AZA). Patients with negative anti-AQP4 titers were excluded. Kaplan-Meier survival analysis was used to estimate proportion of relapse-free patients following initiation of first line immunosuppressive therapy. A Cox proportional hazards regression model assessed the association of risk of relapsing with first-line immunosuppressive treatments with and without adjustments of pre-specified factors (age at disease onset, duration of disease, sex, race, CNS location of relapse). 7 of 29 patients (24%) receiving rituximab experienced a relapse within the first 3 years of treatment vs. 13 of 23 patients (57%) receiving either AZA or MMF. Within the first 6 months of treatment, 2 (6.9%) patients treated with rituximab experienced a relapse vs. 7 (30.4%) patients treated with either MMF or AZA. In the 29 patients treated with rituximab, the 1-year and 3-year proportion of relapse-free patients was 88.8% and 70.9%. For the 23 patients treated with either AZA or MMF, the 1-year and 3-year proportion of relapse-free patients was 69.5% and 38.7%. In the univariate analysis, the risk of relapse was significantly higher in patients treated with AZA or MMF compared to those treated with rituximab (hazard ratio [HR] of 2.48 [0.99 - 6.21]; p=0.046). In this real-world study involving a majority of Black NMOSD patients, rituximab was relatively more effective in preventing relapses within 3 years of therapy initiation than AZA and MMF. Rituximab remains an effective option for treating NMOSD, especially when there are delays in treatment due to access and economic issues associated with newer treatments.

Family perspectives on severe mental disorders and relapse prevention: a qualitative study

Background. The relapse of severe mental disorders is still quite high due to the lack of family knowledge in treating schizophrenic patients. The family treats and prevents the relapse of severe mental disorder by taking the sufferer to spiritual treatment, a shaman, being shackled (pasung) because of the assumption that the cause is evil from ghosts, magic, curses, and unbelief. Objective. The purpose of this study is to explore the experience of families preventing the relapse of severe mental disorders. Materials and Methods. This study is qualitative research with a phenomenological approach. The sampling was conducted by purposive sampling with 9 participants. Data were collected using semi-structured in-depth interviews with audio-recorded, transcribed verbatim, validated, and analyzed based on Colaizzi’s method of data analysis. Results. Four themes were generated, including: i) the perception of severe mental illness; ii) the causes of relapse; iii) family prevention for severe mental disorders relapse; iv) relapse becomes helplessness and a burden on the family. Conclusions. Lack of family knowledge of severe mental disorders, prevention of relapse, and lack of social support causes helplessness and a burden on the family. Increased knowledge, coping skills, and support for families with Schizophrenia are very important to help relapse prevention and the burden that arises.

Multiple Sclerosis Disease Activity and Disability Following Cessation of Fingolimod for Pregnancy.

Discontinuation of fingolimod ≥2 months before pregnancy is recommended to minimize potential teratogenicity. The magnitude of MS pregnancy relapse risk, particularly severe relapses, after fingolimod cessation is unclear, as is whether this risk is reduced by pregnancy or modifiable factors. Pregnancies who stopped fingolimod treatment within 1 year before or during pregnancy were identified from the German MS and Pregnancy Registry. Data were collected through structured telephone-administered questionnaires and neurologists' notes. Severe relapses were defined as a ≥2.0 increase in Expanded Disability Status Scale (EDSS) or new or worsening relapse-related ambulatory impairment. Women who continued to meet this definition 1 year postpartum were classified as reaching the Severe Relapse Disability Composite Score (SRDCS). Multivariable models accounting for measures of disease severity and repeated events were used. Of the 213 pregnancies among 201 women (mean age at pregnancy onset 32 years) identified, 56.81% (n = 121) discontinued fingolimod after conception. Relapses during pregnancy (31.46%) and the postpartum year (44.60%) were common. Nine pregnancies had a severe relapse during pregnancy and additional 3 during the postpartum year. One year postpartum, 11 of these (6.32% of n = 174 with complete EDSS information) reached the SRDCS. Adjusted relapse rates during pregnancy were slightly higher compared with the year before pregnancy (relapse rate ratio = 1.24, 95% CI 0.91-1.68). Neither exclusive breastfeeding nor resuming fingolimod within 4 weeks of delivery were associated with a reduced risk of postpartum relapses. Most pregnancies relapsed during the first 3 months postpartum (n = 55/204, 26.96%). Relapses during pregnancy after fingolimod cessation are common. Approximately 6% of women will retain clinically meaningful disability from these pregnancy-related, fingolimod cessation relapses 1 year postpartum. This information should be shared with women on fingolimod desiring pregnancy, and optimizing MS treatment with nonteratogenic approaches should be discussed.

Involvement of Degenerating 21.5 kDa Isoform of Myelin Basic Protein in the Pathogenesis of the Relapse in Murine Relapsing-Remitting Experimental Autoimmune Encephalomyelitis and MS Autopsied Brain.

Multiple sclerosis (MS) is the chronic inflammatory demyelinating disease of the CNS. Relapsing-remitting MS (RRMS) is the most common type of MS. However, the mechanisms of relapse and remission in MS have not been fully understood. While SJL mice immunized with proteolipid protein (PLP) develop relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), we have recently observed that some of these mice were resistant to the active induction of relapsing EAE after initial clinical and histological symptoms of EAE with a severity similar to the relapsing EAE mice. To clarify the mechanism of relapsing, we examined myelin morphology during PLP139-151-induced RR-EAE in the SJL mice. While RR-EAE mice showed an increased EAE severity (relapse) with CNS inflammation, demyelination with abnormal myelin morphology in the spinal cord, the resistant mice exhibited a milder EAE phenotype with diminished relapse. Compared with the RR-EAE mice, the resistant mice showed less CNS inflammation, demyelination, and abnormalities of the myelin structure. In addition, scanning electron microscopic (SEM) analysis with the osmium-maceration method displayed ultrastructural abnormalities of the myelin structure in the white matter of the RR-EAE spinal cord, but not in that of the resistant mice. While the intensity of myelin staining was reduced in the relapsing EAE spinal cord, immunohistochemistry and immunoblot analysis revealed that the 21.5 kDa isoform of degenerating myelin basic protein (MBP) was specifically induced in the relapsing EAE spinal cord. Taken together, the neuroinflammation-induced degenerating 21 kDa isoform of MBP sheds light on the development of abnormal myelin on the relapse of MS pathogenesis.

Protocolo de tratamiento del brote de esclerosis múltiple

Multiple sclerosis relapses consist of symptoms and signs caused by a new focal or multifocal inflammatory event in the central nervous system and must be distinguished from pseudo-relapses, related to the reappearance of residual symptoms from previous attacks, often in the context of fever or infection. Treating the relapse will hasten short-term recovery but will not modify the prognosis in the long-term. There are no differences between using high-dose oral or parenteral corticosteroids, but follow-up with a tapered oral regimen is not recommended. Mild symptoms (eg, localized sensory symptoms) can be managed on an outpatient basis or left untreated, but corticosteroid therapy is advised for disabling symptoms (eg, optic neuritis, ataxia, ophthalmoplegia, paresis). In the case of severe relapses and in the absence of a response to corticosteroids in the first week, a low threshold is advised so as to indicate plasma exchange, even if the diagnosis of the demyelinating syndrome is not fully established.

Long-term Efficacy of Satralizumab in Adults with Aquaporin-4-IgG-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD): Results from SAkuraMoon (S5.001)

Long-term Efficacy of Satralizumab in Adults with Aquaporin-4-IgG-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD): Results from SAkuraMoon (S5.001)

CDBN-YGXZ, a Novel Small-Molecule Drug, Shows Efficacy against Clostridioides difficile Infection and Recurrence in Mouse and Hamster Infection Models.

Clostridioides difficile infection (CDI) causes severe diarrhea and colitis, leading to significant morbidity, mortality, and high medical costs worldwide. Oral vancomycin, a first-line treatment for CDI, is associated with a high risk of recurrence, necessitating novel therapies for primary and recurrent CDI. A novel small-molecule compound, CDBN-YGXZ, was synthesized by modifying the benzene ring of nitazoxanide with lauric acid. The mechanism of action of CDBN-YGXZ was validated using a pyruvate:ferredoxin/flavodoxin oxidoreductase (PFOR) inhibition assay. The efficacy of CDBN-YGXZ was evaluated using the MIC test and CDI infection model in mice and hamsters. Furthermore, metagenomics was used to reveal the underlying reasons for the effective reduction or prevention of CDI after CDBN-YGXZ treatment. The inhibitory activity against PFOR induced by CDBN-YGXZ. MIC tests showed that the in vitro activity of CDBN-YGXZ against C. difficile ranging from 0.1 to 1.5 μg/mL. In the mouse and hamster CDI models, CDBN-YGXZ provided protection during both treatment and relapse, while vancomycin treatment resulted in severe relapse and significant clinical scores. Compared with global effects on the indigenous gut microbiota induced by vancomycin, CDBN-YGXZ treatment had a mild influence on gut microbes, thus resulting in the disappearance or reduction of CDI recurrence. CDBN-YGXZ displayed potent activity against C. difficile in vitro and in vivo, reducing or preventing relapse in infected animals, which could merit further development as a potential drug candidate for treating CDI.

A series of patients with refractory myasthenia gravis

IntroductionAdvances in the treatment of myasthenia gravis (MG) have improved quality of life and prognosis for the majority of patients. However, 10%–20% of patients present refractory MG, with frequent relapses and significant functional limitations. Patients and methodsPatients with refractory MG were selected from a cohort of patients diagnosed with MG between January 2008 and June 2019. Refractory MG was defined as lack of response to treatment with prednisone and at least 2 immunosuppressants, inability to withdraw treatment without relapse in the last 12 months, or intolerance to treatment with severe adverse reactions. ResultsWe identified 84 patients with MG, 11 of whom (13%) met criteria for refractory MG. Mean (standard deviation) age was 47 (18) years; 64% of patients with refractory MG had early-onset generalised myasthenia (as compared to 22% in the group of patients with MG; P < .01), with a higher proportion of women in this group (P < .01). Disease severity at diagnosis and at the time of data analysis was higher among patients with refractory MG, who presented more relapses during follow-up. Logistic regression analysis revealed an independent association between refractory MG and the number of severe relapses. ConclusionsThe percentage of patients with refractory MG in our series (13%) is similar to those reported in previous studies; these patients were often women and presented early onset, severe forms of onset, and repeated relapses requiring hospital admission during follow-up.

Abstract 3243: Modulating the brain immune system to fight cancer in 3 dimensions

Abstract Despite the remarkable efficiency of immune checkpoint modulators against primary and metastatic brain neoplasms, there is a low percentage of responders and clinical trials report severe immune-mediated side effects and disease relapse. An accumulated body of evidence show that non-tumor cells within the tumor microenvironment (TME), specifically the brain microenvironment (BME), including tumor vasculature and immune stromal cells, such as astrocytes, microglia and pericytes, dictate the overall therapeutic efficacy. We synthesized a biodegradable, off-the-shelf and cost-effective nano-sized polymeric platform that combines a cancer vaccine with the targeted inhibition of molecular and/or cellular immune suppressive players. These precision nano-sized medicines aim to re-educate and harness patient T-cell response against tumors, leading to an immunological memory able to control tumor relapse without any follow-up treatment. The design of these advanced peptide and RNA immunotherapeutics is guided by the identification of lead immune suppressor factors and tumor-specific antigens and proinflammatory cytokines using novel 3D bio-printed brain tumor-immune models developed in our lab. Using this unique model platform we identified P-selectin as a novel immune checkpoint in the brain regulating cancer cells-microglia and tumor-associated macrophages interactions. Combining a P-selectin inhibitor with our first nano-immunotherapy candidates sensitized brain malignancies mouse models to immune-checkpoint modulators, dramatically increasing disease-free survival rates. Citation Format: Eilam Yeini, Daniella Vaskovich-Koubi, Ron Kleiner, Helena F. Florindo, Ronit Satchi-Fainaro. Modulating the brain immune system to fight cancer in 3 dimensions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3243.

The use of the drug Elizaria – a biosimilar of the original eculizumab in atypical hemolytic-uremic syndrome due to mutation of the С3 gene in children: clinical observation and literature review

This article presents the features of atypical haemolytic-uremic syndrome (ORPHA 544472) in children. Atypical haemolytic-uremic syndrome (aHUS) is defined by a triad: haemolytic anaemia, thrombocytopenia and acute kidney injury in pediatric and adult patients. The OMIM catalogue presents the phenotypic series of aHUS with mutations of the C3, CFB, CFH, CFHR1, CFHR3, DGKE, MCP, THBD genes. Atypical haemolytic-uremic syndrome is often associated with gene mutations in proteins and activators that regulate complement. We report the case of a girl who had a manifestation of aHUS at 8 years 5 months of age and a severe relapse at 8 years 10 months of age. The relapse was characterised by manifestations of haemolytic anaemia, thrombocytopenia, acute renal damage, severe arterial hypertension, high lactate dehydrogenase and membrane attack complex levels and low C3 component. After 5 courses of haemodialysis, 3 haemodiafiltration, diuresis increased and biochemical parameters improved. We presented with ASUS in a child associated with a p.Cys1101Tyr C3 gene mutation. We used a complement inhibitor, Elizaria®, a biosimilar to the original drug eculizumab, to treat a child with atypical haemolytic-uremic syndrome due to the C3 gene mutation. The complement system inhibitor therapy with Elizaria preserved the health and life of a sick girl with a severe relapse of aHUS.

Utility of novel viral and immune markers in predicting HBV treatment endpoints: A systematic review of treatment discontinuation studies

Antivirals represent the mainstay of chronic hepatitis B treatment given their efficacy and tolerability, but rates of functional cure remain low during long-term therapy. Treatment discontinuation has emerged as a strategy to maintain partial cure and achieve functional cure in select patient groups. We aimed to evaluate how data from treatment discontinuation studies exploring novel viral and/or immune markers could be applied to the functional cure program. Treatment discontinuation studies evaluating novel viral and/or immune markers were identified by a systematic search of the PubMed database through to October 30, 2022. Data extraction focused on information regarding novel markers, including identified cut-off levels, timing of measurement, and associated effect on study outcomes of virological relapse, clinical relapse, and HBsAg seroclearance. From a search of 4,492 citations, 33 studies comprising a minimum of 2,986 unique patients met the inclusion criteria. Novel viral markers, HBcrAg and HBV RNA, were demonstrated across most studies to be helpful in predicting off-therapy partial cure, with emerging evidence to support a link with functional cure. From novel immune marker studies, we observed that treatment discontinuation has the potential to trigger immune restoration, which may be associated with a transient virological relapse. To this end, these studies support the combination of virus-directing agents with immunomodulator therapies to induce two key steps underlying functional cure: viral antigen load reduction and restoration of the host immune response. Patients with a favourable profile of novel viral and immune markers stand to benefit from a trial of antiviral treatment discontinuation alongside novel virus-directing agents with the aim of achieving functional cure without excessive risk of severe clinical relapse. Select patients with chronic hepatitis B undergoing nucleoside analogue therapy may benefit from a trial of treatment discontinuation, aiming to maintain partial cure and/or achieve functional cure. We propose a profile of novel viral and immune markers to identify patients who are likely to achieve these goals without excessive risk of hepatic decompensation. Furthermore, treatment discontinuation may also be considered as a therapeutic strategy to trigger immune restoration, which may increase the chance of functional cure when used in conjunction with novel virus-directing agents.

Chronic recurrent urticaria in a patient with recurrent herpes labialis: complete remission after administration of aciclovir and antihistamines.

Chronic recurrent urticaria, occurring in the context of infections, represents a major challenge for clinicians. Chronic genital herpes infection has been perceived in the literature as a possible trigger of chronic recurrent urticaria. The administration of a systemic corticosteroid regimen in these cases has no long-lasting effect and the subsequent relapses are difficult to control. In these cases, treatment of the urticaria with antihistamine (as monomedication) is often not sufficient and does not suppress the symptomatology. The administration of acyclovir or valacyclovir according to a specific therapeutic regimen as monotherapy or in combination with antihistamine has been shown to be quite effective. The doses of this administration vary and can be tailored to clinical symptomatology. We present a 41-year-old female patient with chronic recurrent urticaria associated with angioedema and bronchospasm, in whom her herpes genitalis was found to be concurrent within the history and clinical examination. According to the history, the herpes was also recurrent and dated back about a year. Chlamydia trachomatis infection was also found, with serological findings corresponding to vaginal discomfort. Treatment with acyclovir 400mg thrice daily for an initial period of 7 days in combination with desloratadine 5mg daily was started as we observed complete remission of the urticarial rash. Due to worsening vaginal discharge, it was decided to temporarily discontinue systemic acyclovir therapy and treatment for the chlamydial infection was initiated with doxycycline 100 mg twice daily for 21 days. Already on day 1 after stopping acyclovir, a severe relapse with generalization of the urticarial rash was observed. Control of symptomatology was achieved by reintroduction of acyclovir according to the regimen in combination with antihistamine. Chronic infections are one of the common causes of chronic recurrent urticaria with a tendency to generalization and possible complications such as angioedema and bronchospasm. An academic, analytical approach to patients and the consistent exclusion of each possible trigger for chronic recurrent urticaria often guarantee the success of subsequent treatment.

Electronic health record data for assessing risk of hospitalization for COVID-19: Methodological considerations applied to multiple sclerosis.

During the COVID-19 pandemic, electronic health record (EHR) data has been used to investigate disease severity and risk factors for severe COVID-19 in people with multiple sclerosis (pwMS). Methodological challenges including sampling bias, and residual confounding should be considered when conducting EHR-based studies. We aimed to address these limitations related to the use of EHR data in order to identify risk factors, including the use of disease modifying therapies (DMTs), associated with hospitalization for COVID-19 amongst pwMS. We performed a retrospective cohort study including a sample of 47,051 pwMS using a large US-based EHR and claims linked database. Follow-up started at the beginning of the pandemic, February 20th 2020, and continued until September 30th 2020. COVID-19 diagnosis was determined by the presence of ICD-10 diagnostic code for COVID-19, or a positive diagnostic laboratory test, or an ICD-10 diagnostic code for coronaviruses. We used Cox regression modeling to assess the impact of baseline demographics, MS disease history and pre-existing comorbidities on the risk of hospitalization for COVID-19. Then, we identified 5,169 pwMS using ocrelizumab (OCR) and 3,351 pwMS using dimethyl fumarate (DMF) at baseline, and evaluated the distribution of the identified COVID-19 risk factors between the two groups. Finally, we used Cox regression models, adjusted for the identified confounders, to estimate the risk of hospitalization for COVID-19 in pwMS treated with OCR compared to DMF. Among the pwMS cohort, we identified 799 COVID-19 cases (1.7%) which resulted in 182 hospitalizations for COVID-19 (0.4%). Population differences between the pwMS and COVID-19 cohorts were observed. Statistical modeling identified older age, male gender, African-American race, walking with assistance, non-ambulatory status, severe relapse requiring hospitalization in year prior to baseline, and specific comorbidities to be associated with a higher risk of COVID-19 related-hospitalization. Comparing the COVID-19 risk factors between OCR users and DMF users, MS characteristics including ambulatory status and MS subtype were highly imbalanced, likely arising from key differences in the labelled indications for these therapies. Compared to DMF use, in unadjusted (HR 1.58, 95% CI 0.73 - 3.44), adjusted (HR 1.28, 95% CI 0.58 - 2.83), propensity score weighted (HR 1.25, 95% CI 0.56 - 2.80), and doubly robust models (HR 1.29, 95% CI 0.57 - 2.89), no significantly increased risk of hospitalization for COVID-19 was associated with OCR use. We observed significant population differences when comparing all pwMS to COVID-19 cases, as well as significant differences in key confounders between OCR and DMF treated patients. In unadjusted analyses we did not observe a statistically significant higher risk of COVID-19 hospitalization in pwMS treated with OCR compared to DMF, with further attenuation of risk when adjusting for the key confounders. This study re-emphasises the importance to appropriately consider both sampling and confounding bias in EHR-based MS research.