[Therapeutic Strategies and Disease-Modifying Therapies for Multiple Sclerosis].

Multiple sclerosis is an inflammatory demyelinating disease of unknown cause that affects the central nervous system. Although it was once deemed "incurable," many disease-modifying therapies have been introduced since the beginning of the 20th century; eight of these are now available in Japan. Treatment for multiple sclerosis is undergoing a significant shift from the safety-oriented "escalation strategy," in which the patient is initially administered medications with low risks of side effects but moderate efficacy, to a "personalized approach" based on individual prognostic factors followed by an "early top-down strategy" in which higher efficacy treatments are initiated first. Disease-modifying drugs for multiple sclerosis can be high- (fingolimod, ofatumumab, natalizumab) or moderate-efficacy (interferon beta, glatiramer acetate, dimethyl fumarate), and there are also disease-modifying therapies for secondary progressive multiple sclerosis (siponimod and ofatumumab). Approximately 20,000 Japanese patients have multiple sclerosis, and this number continues to increase. Many neurologists are expected to prescribe high-efficacy drugs in the future. The risk management of adverse events, particularly progressive multifocal leukoencephalopathy, is required to ensure that the importance of safety never be underestimated, even though treatment efficacy is the main focus.

Compromiso cardíaco en el síndrome inflamatorio multisistémico post SARS-CoV-2 en niños / Cardiac involvement in post-SARS-CoV-2 multisystem inflammatory syndrome in children / Envolvimento cardíaco na síndrome inflamatória multissistêmica pós-SARS-CoV-2 em crianças

Objetivo: describir las características de ocho pacientes pediátricos que se presentaron con síndrome inflamatorio multisistémico (MIS-C) asociado a SARS-CoV-2 y compromiso cardíaco. Material y métodos: estudio descriptivo, retrospectivo de ocho pacientes con edades entre 1 y 13 años, con diagnóstico de MIS-C y compromiso cardíaco, asistidos en el CHPR. Se analiza su historia clínica, evolución y tratamiento. Resultados: los pacientes presentaron fiebre en el 100%, exantema e hiperemia conjuntival en el 88%, síntomas digestivos en el 50%, insuficiencia respiratoria en el 25% y shock en el 50%. Todos requirieron ingreso a cuidados intensivos. La alteración de la contractilidad cardíaca estuvo presente en el 63% de los pacientes, fue leve y segmentaria en el 80%, el 60% requirió soporte inotrópico por 3 días, recuperando una función normal en 7 días. La insuficiencia mitral se presentó en el 25% y el derrame pericárdico en el 38%, ambos de grado leve. Un paciente presentó dilatación de arterias coronarias con Z score < 2. El 85% de los pacientes presentó alteraciones del ECG, en el 29% se trató de alteración en la repolarización, en el 29% intervalo QTc prolongado, en el 15% bloqueo atrioventricular de 1er grado y bloqueo incompleto de rama derecha. Un paciente tuvo fibrilación auricular por 3 días con remisión espontánea a ritmo sinusal. Las troponinas estuvieron altas en el 57% de los pacientes y el ProBNP elevado en el 100%. Todos recibieron inmunoglobulinas, metilprednisolona y aspirina. Conclusiones: se presentaron ocho pacientes pediátricos con MIS-C y compromiso cardíaco, el 50% se presentó en shock, todos requirieron ingreso a cuidados intensivos. El 85% presento alteraciones en el ECG. El 63% presentó compromiso de la contractilidad sectorial y leve, se normalizó en 7 días. El 60% requirió soporte inotrópico por una media de 3 días.

Objective: describe the characteristics of 8 children who presented Multisystem Inflammatory Syndrome associated with SARS-CoV2 infections (MIS-C) and cardiac involvement. Material and methods: descriptive, retrospective study of 8 patients of between 1 and 13 years of age, diagnosed with MIS-C and cardiac involvement, assisted at the Pereira Rossell Children Hospital, analysis of their medical records, evolution and treatment. Results: the patients showed: fever in 100% of the cases, rash and conjunctival hyperemia in 88%, digestive symptoms in 50%, respiratory failure in 25% and shock in 50%. All required admission to Intensive Care. Cardiac contractility alteration was present in 63% of patients, the affectation was mild and segmental in 80%, 60% required inotropic support for 3 days and recovered normal functions in 7 days. Mitral regurgitation was present in 25% of the cases and pericardial effusion in 38%, mild in both cases. One patient had dilated coronary arteries with a Z score <2. 85% of the patients presented ECG abnormalities, 29% present alteration of repolarization, 29% prolonged QTc, 15% 1st degree atrioventricular block and incomplete right bundle branch block. One patient had atrial fibrillation for 3 days with spontaneous remission to sinus rhythm. Troponins were increased in 57% of the patients and ProBNP elevated in 100%. All patients received Immunoglobulins, Methylprednisolone and Aspirin. Conclusions: we present eight pediatric patients with MIS-C and cardiac involvement, 50% suffered shock, all required admission to Intensive Care. ECG abnormalities were found in 85% of the patients. Mild and segmental contractility compromise was found in 63% of the patients and normalized in 7 days. 60% required inotropic support for a mean of 3 days.

Objetivo: descrever as características de 8 pacientes pediátricos que apresentaram Síndrome Inflamatória Multissistêmica (MIS-C) associada ao SARS-CoV-2 e comprometimento cardíaco. Material e métodos: estudo descritivo, retrospectivo, de oito pacientes com idade entre 1 e 13 anos, com diagnóstico de MIS-C e comprometimento cardíaco, assistidos pelo CHPR. Seu prontuário médico, evolução e tratamento são analisados. Resultados: os pacientes apresentaram febre em 100%, erupção cutânea e hiperemia conjuntival em 88%, sintomas digestivos em 50%, insuficiência respiratória em 25% e choque em 50%. Todos necessitaram de internação nos cuidados intensivos. A alteração da contratilidade cardíaca esteve presente em 63% dos pacientes, foi leve e segmentar em 80%, 60% necessitaram de suporte inotrópico por 3 dias, recuperando a função normal em 7 dias. A regurgitação mitral ocorreu em 25% dos pacientes e o derrame pericárdico em 38%, ambos de grau leve. Um paciente apresentou dilatação da artéria coronária com escore Z < 2. 85% dos pacientes apresentaram anormalidades no ECG, 29% foram alterações de repolarização, 29% intervalo QTc prolongado em bloqueio atrioventricular de 1º grau a 15% e bloqueio incompleto do ramo direito. Um paciente apresentou fibrilação atrial por 3 dias com remissão espontânea ao ritmo sinusal. As troponinas foram elevadas em 57% dos doentes e ProBNP elevado em 100%. Todos receberam imunoglobulinas, Metilprednisolona e aspirina. Conclusões: houve oito pacientes pediátricos com SMIM-C e comprometimento cardíaco, 50% em choque, todos necessitaram de internação em terapia intensiva. 85% apresentaram elevações no ECG. 63% apresentaram comprometimento setorial e de contratilidade leve, normalizados em 7 dias. 60% necessitaram de suporte inotrópico por uma média de 3 dias.

Immunomodulatory and Antitumoral Activity of Gold Nanoparticles Synthesized by Red Algae Aqueous Extracts.

This study reports on the green and cost-efficient synthesis of gold nanoparticles from three different red algae extracts. The nanoparticles synthesized were fully characterized by UV-Vis spectroscopy, HRTEM, and Z-potential. Relevant components occurring in the extracts, such as polysaccharides or phenolic content, were assessed by analytical techniques such as spectrophotometric assays and liquid chromatography. Finally, the antioxidant, antitumoral, and anti-inflammatory potential of both the extracts and the gold nanoparticles synthesized were analyzed in order to determine a possible synergistic effect on the nanoparticles. The results obtained confirmed the obtainment of gold nanoparticles with significant potential as immunotherapeutic agents. The therapeutic potential of these nanoparticles could be higher than that of inert gold nanoparticles loaded with bioactive molecules since the former would allow for higher accumulation into the targeted tissue.

Probiotic peanut oral immunotherapy versus oral immunotherapy and placebo in children with peanut allergy in Australia (PPOIT-003): a multicentre, randomised, phase 2b trial.

BACKGROUND: Oral immunotherapy is effective at inducing desensitisation to allergens and induces sustained unresponsiveness (ie, clinical remission) in a subset of patients, but causes frequent reactions. We aimed to investigate whether addition of a probiotic adjuvant improved the efficacy or safety of peanut oral immunotherapy. METHODS: PPOIT-003, a multicentre, randomised, phase 2b trial, was conducted in three tertiary hospitals in Australia (Adelaide [SA], Melbourne [VIC], and Perth [WA]) in children aged 1-10 years, weighing more than 7 kg, with peanut allergy confirmed by a double-blind placebo-controlled food challenge (cumulative 4950 mg dose of peanut protein) and positive peanut skin prick test (≥3 mm) or peanut-specific IgE (≥0·35 kU/L). Children were randomly assigned (2:2:1) to receive probiotic and peanut oral immunotherapy (PPOIT), placebo probiotic and peanut oral immunotherapy (OIT), or placebo probiotic and placebo OIT (placebo) for 18 months, and were followed up until 12 months after completion of treatment. Oral immunotherapy consisted of increasing doses of peanut protein (commercially available food-grade 12% defatted peanut flour [50% peanut protein]) until a 2000 mg daily maintenance dose was reached. The probiotic adjuvant was a daily dose of 2 × 1010 colony-forming units of the probiotic Lactobacillus rhamnosus ATCC 53103. Placebo immunotherapy comprised maltodextrin, brown food colouring, and peanut essence, and placebo probiotic was maltodextrin. Dual primary outcomes were 8-week sustained unresponsiveness, defined as no reaction to a cumulative dose of 4950 mg peanut protein at treatment completion and 8 weeks after treatment completion, in the PPOIT versus placebo groups and the PPOIT versus OIT groups, analysed by intention to treat. Safety endpoints were adverse events during the treatment phase, and peanut ingestion and reactions in the 12-month post-treatment period. This study is registered with the Australian New Zealand Clinical Trials Registry, 12616000322437. FINDINGS: Between July 4, 2016, and Sept 21, 2020, 201 participants were enrolled and included in the intention-to-treat analysis. 36 (46%) of 79 children in the PPOIT group and 42 (51%) of 83 children in the OIT group achieved sustained unresponsiveness compared with two (5%) of 39 children in the placebo group (risk difference 40·44% [95% CI 27·46 to 53·42] for PPOIT vs placebo, p<0·0001), with no difference between PPOIT and OIT (-5·03% [-20·40 to 10·34], p=0·52). Treatment-related adverse events were reported in 72 (91%) of 79 children in the PPOIT group, 73 (88%) of 83 children in the OIT group, and 28 (72%) of 39 children in the placebo group. Exposure-adjusted incidence of adverse events was 10·58 in the PPOIT group, 11·36 in the OIT, and 2·09 in the placebo group (ratio 0·92 [95% CI 0·85 to 0·99] for PPOIT vs OIT, p=0·042; 4·98 [4·11-6·03] for PPOIT vs placebo, p<0·0001; 5·42 [4·48-6·56] for OIT vs placebo, p<0·0001), with differences seen primarily in gastrointestinal symptoms and in children aged 1-5 years. During the 12-month post-treatment period, 60 (85%) of 71 participants in the PPOIT group, 60 (86%) of 70 participants in the OIT group, and six (18%) of 34 participants in the placebo group were eating peanut; rescue epinephrine use was infrequent (two [3%] of 71 in the PPOIT group, four [6%] of 70 in the OIT group, and none in the placebo group). INTERPRETATION: Both PPOIT and OIT were effective at inducing sustained unresponsiveness. Addition of a probiotic did not improve efficacy of OIT, but might offer a safety benefit compared with OIT alone, particularly in preschool children. FUNDING: National Health and Medical Research Council Australia and Prota Therapeutics.

Characterization of Alpinia officinarum Hance polysaccharide and its immune modulatory activity in mice.

This study aimed to characterize the structural features of a novel water-soluble polysaccharide (AOHP) extracted from Alpinia officinarum Hance and to verify its regulating effect on mouse immunity. Cellulose DEAE-52 and Sephadex G-100 columns were used to obtain purified AOHP. Techniques including NMR, methylation, monosaccharide composition, FT-IR, and molecular weight determination were applied to investigate the physicochemical properties and structural characterization of AOHP. Then, the influence of AOHP on mice was studied. After oral administration of AOHP, organ indexes, serum biochemistry indexes, and cytokines in the spleens of the mice were analysed. The results showed that AOHP was composed of T-α-D-Glcp, (1,4)-α-D-Glcp and (1,4,6)-α-D-Glcp with a number-average molecular weight of 26.0 kDa and a weight-average molecular weight of 52.8 kDa. Additionally, the innate immune statuses of the mice were improved by treatment with AOHP, while no obvious damage was identified. To conclude, the immunomodulatory activity and biological safety make AOHP a viable candidate as an ingredient for healthcare drugs.

Oral administration of Lactobacillus delbrueckii enhances intestinal immunity through inducing dendritic cell activation in suckling piglets.

Lactobacillus delbrueckii (LAB) has been demonstrated to exert versatile beneficial effects on modulating intestinal immunity, increasing gut microbial diversity, promoting growth performance, and even preventing disease onset in pigs. However, the underlying mechanism of LAB-mediated gut immunity regulation in piglets remains unclear. In this study, we found that supplementation of LAB significantly increases serum TNF-α, ileum IL-4, and IL-10 levels compared with the control group. Meanwhile, oral supplementation of LAB-modified gut microbial communities was evidenced by the increased abundance of the Lactobacillus genus in the colon. Mechanistically, LAB induced dendritic cell (DC) maturation and activation, which may be relevant to the activation of NF-κB and MAPK signaling pathways. Moreover, we found that oral administration of LAB during the suckling period shows long-lasting immunomodulatory impacts on intestinal immunity after weaning. Collectively, this study uncovers the mechanism of LAB in regulating the intestinal immunity of piglets, suggesting that LAB can be developed as an immunoenhancing biological agent during the suckling period.

Preemptive Interferon-α Therapy Could Protect Against Relapse and Improve Survival of Acute Myeloid Leukemia Patients After Allogeneic Hematopoietic Stem Cell Transplantation: Long-Term Results of Two Registry Studies.

For allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, preemptive interferon-α (IFN-α) therapy is considered as a useful method to eliminate the minimal residual disease (MRD). Our purpose is to assess the long-term efficacy of preemptive IFN-α therapy in acute myeloid leukemia (AML) patients following allo-HSCT based on two registry studies (#NCT02185261 and #NCT02027064). We would present the final data and unpublished results of long-term clinical outcomes with extended follow-up. We adopted polymerase chain reaction (PCR) and multiparameter flow cytometry (MFC) to monitor MRD, and a positive result of bone marrow specimen examined by either of them would be identified as the MRD-positive status. Subcutaneous injections of recombinant human IFN-α-2b were performed for 6 cycles, and prolonged IFN-α therapy could be permitted at the request of patients. The median cycles were 3.5 (range, 0.5-30.5) cycles. A total of 9 patients suffered from grade ≥3 toxicities (i.e., infectious: n = 6; hematologic: n = 3). The 6-year cumulative incidences of relapse and non-relapse mortality following IFN-α therapy were 13.0% (95% confidence interval [CI], 5.4-20.6%) and 3.9% (95%CI, 0.0-17.6%), respectively. The probability of disease-free survival at 6 years following IFN-α therapy was 83.1% (95%CI, 75.2-91.9%). The probability of overall survival at 6 years following IFN-α therapy was 88.3% (95%CI, 81.4-95.8%). The cumulative incidences of total chronic graft-versus-host disease (cGVHD) and severe cGVHD at 6 years following IFN-α therapy were 66.2% (95%CI, 55.5-77.0%) and 10.4% (95%CI, 3.6-17.2%), respectively. Multivariable analysis showed that an alternative donor was associated with a lower risk of relapse and the better disease-free survival. Thus, preemptive IFN-α therapy could clear MRD persistently, prevent relapse truly, and improve long-term survival in AML patients following allo-HSCT.

Progressive, refractory macrophage activation syndrome as the initial presentation of anti-MDA5 antibody positive juvenile dermatomyositis: a case report and literature review.

BACKGROUND: Macrophage activation syndrome (MAS) is a severe and under-recognized complication of rheumatologic diseases. We describe a patient who presented with rapidly progressive, refractory MAS found to have anti-MDA5 antibody Juvenile Dermatomyositis (JDM) as her underlying rheumatologic diagnosis. CASE PRESENTATION: We describe a 14-year-old female who at the time of admission had a history of daily fevers for 6 weeks and an unintentional sixteen-pound weight loss. Review of systems was significant for cough, shortness of breath, chest pain, headaches, sore throat, muscle aches, rash, nausea, and loss of appetite. An extensive initial workup revealed findings consistent with an autoimmune process. While awaiting results of her workup she had clinical decompensation with multi-organ system involvement including pancytopenias, interstitial lung disease, hepatitis, cardiac involvement, gastrointestinal distension and pain, feeding intolerance, extensive mucocutaneous candidiasis, and neuropsychiatric decline. Due to her decompensation, significant interstitial lung disease, and likely underlying rheumatologic condition she was started on high dose pulse steroids and mycophenolate. An MRI was performed due to her transaminitis and shoulder pain revealing significant myositis. Intravenous immunoglobulin was then initiated. The myositis antibody panel sent early in her workup was significant for anti-MDA5 and anti-SSA-52 antibodies. Despite high dose pulse steroids, mycophenolate, and IVIG, her disease progressed requiring escalating therapies. Ultimately, she responded with resolution of her MAS as well as significant and steady improvement in her feeding intolerance, interstitial lung disease, cardiac dysfunction, myositis, arthritis, and cutaneous findings. CONCLUSIONS: JDM in the pediatric patient is rare, as is MAS. In patients with complex rheumatologic conditions and lack of response to treatment, it is important to continually assess the patient's clinical status with MAS in mind, as this may change the treatment approach. Without proper recognition of this complication, patients can have a significant delay in diagnosis leading to life-threatening consequences.

Clinical features, investigations, and outcomes of pediatric limbic encephalitis: A multicenter study.

OBJECTIVES: To describe the clinical presentation, investigations, management, and disease course in pediatric autoimmune limbic encephalitis (LE). METHODS: In this retrospective observational study, from the UK Childhood Neuroinflammatory Disease network, we identified children from six tertiary centers with LE <18 years old between 2008 and 2021. Clinical and paraclinical data were retrieved from medical records. RESULTS: Twenty-five children fulfilling LE criteria were identified, with median age of 11 years (IQR 8, 14) and median follow-up of 24 months (IQR 18, 48). All children presented with seizures; 15/25 (60%) were admitted to intensive care. Neuroimaging demonstrated asymmetric mesial temporal changes in 8/25 (32%), and extra-limbic changes with claustrum involvement in 9/25 (38%). None were positive for LGI1/CASPR2 antibodies (Abs), 2/25 were positive for serum anti-NMDAR Abs, and 2/15 positive for anti-Hu Abs; one died from relapsing neuroblastoma. Two children had serum and CSF anti-GAD antibodies. Initial immune therapy included steroids in 23/25 (92%), intravenous immunoglobulin (IVIg) in 14/25 (56%), and plasma exchange in 7/25 (28%). The commonest second-line treatment was rituximab in 15/25 (60%). Median duration of hospital admission was 21 days (IQR 11, 30). At last follow-up, 13/25 (52%) had refractory seizures and 16/25 (64%) had memory impairment. Six children (24%) had modified Rankin Scale (mRS) scores ≥3. There was no significant difference in mRS, or long-term cognitive and epilepsy outcomes in those who received rituximab versus those who did not. INTERPRETATION: A diagnosis of autoimmune LE was associated with significant morbidity and adverse outcomes in this pediatric cohort.

Induction Immunotherapy Followed by Thoracic Radiation without Chemotherapy in Unresectable Stage III Non-Small Cell Lung Cancer: A Case Series.

OBJECTIVE: Although concurrent chemoradiation has been the standard of care for unresectable stage III non-small cell lung cancer (NSCLC) due to increased survival and decreased disease progression, patients with poor performance status cannot tolerate chemotherapy toxicity well. Durvalumab, an immune checkpoint inhibitor targeting the programmed death receptor-1 (PD-1) / programmed death-ligand 1 (PD-L1) axis, demonstrated efficacy as maintenance therapy after definitive chemoradiation. However, the role of immunotherapy in those who cannot tolerate chemoradiation is unclear. METHODS: This retrospective case series reports adult patients with PD-L1-expressing stage III NSCLC diagnosed at Parkview Cancer Institute from 2019-2021 and treated initially with pembrolizumab followed by sequential consolidation chest radiation (CXRT) without cytotoxic chemotherapy. RESULTS: Four cases of stage IIIA squamous cell carcinoma were disease-controlled by this approach, with two partial and one complete response. One case of stage IIIC adenocarcinoma had progressive disease with brain metastasis prior to CXRT. CONCLUSION: This case series suggests that pembrolizumab with sequential CXRT may be beneficial for stage III NSCLC patients with high PD-L1 expression, but additional studies are needed to confirm this hypothesis.

A case of bilateral limbic and recurrent unilateral cortical encephalitis with anti-myelin oligodendrocyte glycoprotein antibody positivity.

BACKGROUND: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody can be detected not only in acute disseminated encephalomyelitis or optic neuritis but also in limbic or cortical encephalitis. However, no previous reports have demonstrated a relapsing case of these two types of encephalitis. CASE REPORT: An 11-year-old girl presented with fever, headache, abnormal behavior, focal impaired awareness seizures (FIAS) on the left side, and MRI hyperintensities in the bilateral amygdala, hippocampus, and right posterior temporal cortex. The symptoms were alleviated with two courses of intravenous methylprednisolone (IVMP) and one course of immunoglobulin. At 16 years of age, the patient returned with left-sided headache and MRI hyperintensities in the left temporal, parietal, and insular cortices, which improved after 3 courses of IVMP. Oral prednisolone (PSL) was tapered over 6 months, when FIAS reappeared on the right side of the body. MRI showed recurrence in the same regions as in the second episode. She received 3 courses of IVMP, followed by gradually tapered PSL without relapse for 1.5 year. Anti-MOG antibodies were positive in both serum and the cerebrospinal fluid prior to treatment in all three episodes. CONCLUSION: Our results revealed that anti-MOG antibody-related bilateral limbic and unilateral cortical encephalitis can manifest with a variety of phenotypes over time in the same patient.

Hypogammaglobulinemia and Infections in Patients With Multiple Sclerosis Treated With Rituximab.

BACKGROUND AND OBJECTIVES: To determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX). METHODS: This prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months. RESULTS: We included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0-36], median Expanded Disability Status Scale 5 [range 0-8], median follow-up 3.5 years [range 1-5.8], and median number of RTX infusions 5 [range 1-9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0-33.1) were free of any infection and 92.0% (95% CI 87.1-97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75-0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05-1.75, p = 0.01). DISCUSSION: In PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection.

Efficacy and safety of an anti-CD20 monoclonal antibody, rituximab, for lupus nephritis: A meta-analysis.

BACKGROUND: The efficacy and safety of rituximab (RTX) for lupus nephritis are still a controversial issue. METHODS: We systematically searched MEDLINE, EMBASE, and the Cochrane Library databases for all clinical controlled studies. RESULTS: Six studies with 588 patients were included in our meta-analysis. RTX increased total renal remission rates (TR, odds ratio [OR] 2.16, 95% CI 1.31 to 3.55, P = .003) and complete renal remission rate (CR, OR 2.42, 95% CI 1.18 to 4.94, P = .02) compared with the control group. Subgroup analyses showed that rituximab was more effective at increasing the rate of TR and CR for lupus nephritis patients compared with mycophenolate mofetil (TR, OR 4.6, 95% CI 1.29 to 16.47, P = .02; CR, OR 2.56, 95% CI 1.19 to 5.47, P = .02) and cyclophosphamide (TR, OR 2.89, 95% CI 1.31 to 6.40, P = .009; CR, OR 2.75, 95% CI 1.19 to 6.4, P = .02). Rituximab also had advantage in reducing Systemic Lupus Erythematosus Disease Activity Index score (-2.49, 95% CI -3.77 to -1.22, P = .0001). There were no significant differences between the RTX group and control group on the change of proteinuria (-0.36 g/d, 95% CI -0.71 to -0.00 g/d, P = .05) and serum creatinine (0.13 mg/dL, 95% CI -0.15 to 0.42 mg/dL, P = .36). RTX treatment did not increase the risk of adverse events compared to the control group. CONCLUSIONS: This study provides clear beneficial effects of RTX in patients with lupus nephritis. In addition, RTX therapy did not increase the risk of adverse events compared to the control group.

Beneficial effects of novel aureobasidium pullulans strains produced beta-1,3-1,6 glucans on interleukin-6 and D-dimer levels in COVID-19 patients; results of a randomized multiple-arm pilot clinical study.

OBJECTIVE: In this pilot clinical study, we report the beneficial effects of beta glucans derived from two strains AFO-202 and N-163 of a black yeast Aureobasidium pullulans on the biomarkers for cytokine storm and coagulopathy in COVID-19 patients. METHODS: A total of 24 RT-PCR positive COVID-19 patients were recruited and randomly divided into three groups (Gr): Gr. 1 control (n = 8) - Standard treatment; Gr. 2: Standard treatment + AFO-202 beta glucan (n = 8); and Gr. 3, Standard treatment + combination of AFO-202 and N-163 beta glucans (n = 8) for 30 days. RESULTS: There was no mortality or requirement of ventilation of the subjects in any of the groups. There was a decrease in D-Dimer values (751 ng/ml to 143.89 ng/ml) and IL-6 values (7.395-3.16 pg/ml) in Gr. 1 in 15 days but the levels increased to abnormal levels on day 30 (D-Dimer: 202.5 ng/ml; IL-6 55.37 pg/ml); which steadily decreased up to day 30 in groups 2 (D-dimer: 560.99 ng/dl to 79.615; IL-6: 26.18-3.41 pg/ml) and 3 (D-dimer: 1614 ng/dl to 164.25 ng/dl; IL-6: 6.25-0.5 pg/ml). The same trend was observed with ESR. LCR and LeCR increased while NLR decreased significantly in Gr. 3. CD4 + and CD8 + T cell count showed relatively higher increase in Gr.3. There was no difference in CRP within the groups. CONCLUSION: As these beta glucans are well known food supplements with a track record for safety, larger multi-centric clinical studies are recommended to validate their use as an adjunct in the management of COVID-19 and the ensuing long COVID-19 syndrome.

All-trans retinoic acid plus low-dose rituximab vs low-dose rituximab in corticosteroid-resistant or relapsed ITP.

The study aimed to compare the efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) patients. Recruited patients were randomized at a ratio of 2:1 into 2 groups: 112 patients received LD-RTX plus ATRA, and 56 patients received LD-RTX monotherapy. Overall response (OR), defined as achieving a platelet count of ≥30 × 109/L confirmed on ≥2 separate occasions (≥7 days apart), at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding within 1 year after enrollment, was observed in more patients in the LD-RTX plus ATRA group (80%) than in the LD-RTX monotherapy group (59%) (between-group difference, 0.22; 95% CI, 0.07-0.36). Sustained response (SR), defined as maintenance of a platelet count >30 × 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment for 6 consecutive months after achievement of OR during 1 year following enrollment, was achieved by 68 (61%) patients in the combination group and 23 (41%) patients in the monotherapy group (between-group difference, 0.20; 95% CI, 0.04-0.35). The 2 most common adverse events (AEs) for the combination group were dry skin and headache or dizziness. Our findings demonstrated that ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a promising treatment option for corticosteroid-resistant or relapsed adult ITP. This study is registered at www.clinicaltrials.gov as #NCT03304288.

Oral/oesophageal candidiasis is a risk factor for severe infection after kidney transplantation.

AIM: Bacterial and fungal infections are serious, life-threatening conditions after kidney transplantation. The development of oral/oesophageal candidiasis after kidney transplantation is not a reported risk factor for subsequent severe infection. This study was performed to investigate the relationship between oral/oesophageal candidiasis after kidney transplantation and the development of subsequent infection requiring hospitalization. METHODS: This retrospective study included 522 consecutive patients who underwent kidney transplantation at Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital from 1 January 2010 to 1 February 2019. Ninety-five percentage of patients were living donor transplant recipients. Visual examination was performed to detect oral candidiasis, beginning immediately after kidney transplantation; upper gastrointestinal endoscopy was performed 8-10 months after kidney transplantation. Twenty-five patients developed candidiasis (Candida-onset group) and 497 did not (non-Candida-onset group). The follow-up periods were 67 (37-86) months in the Candida-onset group and 55 (34-89) months in the non-Candida-onset group. Severe infection was defined as bacterial or fungal infection requiring hospitalization; viral infections were excluded. RESULTS: Severe infection developed in 9/25 (36%) patients in the Candida-onset group and in 77/497 (15%) patients in the non-Candida-onset group (p = .006). Binomial logistic analysis revealed that Candida infection (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.06-6.06; p = .037) and use of rituximab (OR 1.81, 95% CI 1.12-2.93; p = .016) were significant predictors of subsequent severe infection. CONCLUSION: Oral/oesophageal candidiasis is a risk factor for severe infection after kidney transplantation and suggests an over-immunosuppressive state, which should prompt evaluation of immunosuppression.

Current treatment of recurrent pericarditis: safety considerations and future directions.

INTRODUCTION: Recurrent pericarditis is one of the most troublesome complications of pericarditis affecting a substantial amount of patients and often severely impairing the quality of life. Current medical treatments range from non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids to biological agents (anti IL-1 agents, especially anakinra and rilonacept), intravenous immunoglobulins and immunosuppressive treatments. Safety is a major issue to deal with since the disease often affects relatively young or middle-aged patients. AREAS COVERED: The review is aimed at providing an update on the efficacy and safety of current medical therapies for recurrent pericarditis including most recent advances represented by anti IL-1 agents. EXPERT OPINION: Therapy of recurrent pericarditis has evolved over years leading to a more evidence-based and personalized treatment based on clinical presentation and pathophysiology. The main distinction is between patients with an inflammatory phenotype (e.g. fever, elevation of markers of inflammation, pericardial, and/or pleural effusion) vs. those without an inflammatory phenotype. Colchicine and anti IL-1 agents are especially efficacious and indicated for those with an inflammatory phenotype, while corticosteroids, azathioprine, and immunoglobulins seem more indicated for those without evidence of systemic inflammation.

Risk Factors of Coronary Artery Aneurysms in Kawasaki Disease with a Low Risk of Intravenous Immunoglobulin Resistance: An Analysis of Post RAISE.

OBJECTIVE: To detect risk factors of coronary artery aneurysm (CAA) development in patients with Kawasaki disease determined to have a low risk for resistance to primary intravenous immunoglobulin (IVIG) treatment based on the Kobayashi score. STUDY DESIGN: This study included 1757 predicted IVIG responders from Prospective Observational study on STRAtified treatment with Immunoglobulin plus Steroid Efficacy for Kawasaki disease (Post RAISE), a large-scale, multicenter, prospective cohort study of Kawasaki disease in Japan. Predicted IVIG responders were defined as patients with Kawasaki disease with a Kobayashi score of <5, a predictive scoring system for IVIG resistance created in Japan. The primary outcome was CAA development at 1 month after disease onset. CAA was defined as a Z score of ≥2.5. Multivariable logistic regression was used to identify the independent risk factors of CAA. The variables for inclusion were identified based on univariate analysis results and previously reported risk factors of CAA. RESULTS: Among 1632 patients who had complete coronary outcome data, CAA developed in 90 patients (5.5%) at 1 month after disease onset. Multivariable analysis found that a baseline maximum Z score of >2.5, age of <12 months at fever onset, and nonresponsiveness to IVIG were significant, independent risk factors of CAA development at 1 month after disease onset. Among the risk factors, a baseline maximum Z score of >2.5 was most strongly associated with CAA development (OR, 7.1; 95% CI, 4.1-12.2; P ≤ .001). CONCLUSIONS: Predicted IVIG responders with CAA risk factors identified in this study may be candidates for future clinical trials of intensified primary IVIG treatment with prednisolone, cyclosporine or infliximab.