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Background: The incidence of refractory Mycoplasma pneumoniae pneumonia (RMPP) in children is increasing, posing a serious threat to life safety. Intravenous immunoglobulin (IVIG) has demonstrated the ability to modulate the immune system and has shown the potential to treat RMPP. This study evaluated the clinical efficacy and safety of azithromycin combined with IVIG in the treatment of RMPP in children through a meta-analysis., Methods: A comprehensive search was conducted in seven databases including PubMed and Cochrane Library, and the studies on the treatment of RMPP in children with azithromycin combined with IVIG were screened. After data extraction, meta-analysis and sensitivity analysis were performed to assess heterogeneity and stability., Results: Thirteen randomized controlled trials and two cohort studies were included, totaling 1,142 children. The results of meta-analysis showed a higher clinical efficacy rate (RR = 1.18, 95% CI: 1.11-1.25, P < 0.01) and shorter time to defervescence (MD = -2.12, 95% CI: -2.69--1.55), time to disappearance of pulmonary rales (MD = -2.90, 95% CI: -3.57--2.23), time to disappearance of cough (MD = -3.59, 95% CI: -4.51--2.67), and hospital length of stay (MD = -5.72, 95% CI: -8.80--2.64) in the experimental group receiving azithromycin combined with IVIG treatment compared to the control group treated with azithromycin alone. Additionally, there was no significant publication bias in this meta-analysis., Conclusion: Treatment with azithromycin combined with IVIG is more effective than treatment with azithromycin alone for children with RMPP., Clinical Trial Number: Not applicable., (© 2024. The Author(s).)

Background and Objectives: Although rituximab failed to demonstrate a significant effect on disability progression in primary progressive multiple sclerosis (PPMS), ocrelizumab succeeded. Our main objective was to analyze confirmed disability progression (CDP) in a cohort of patients with PPMS treated with anti-CD20 therapies compared with a weighted untreated control cohort., Methods: This was a retrospective study using data from the French MS registry (Observatoire Français de la Sclérose En Plaques). We included patients with PPMS treated or never treated with anti-CD20 therapies from 2016 to 2021, with an Expanded Disability Status Scale score of ≤6.5 at baseline. The primary outcome was time to first CDP. The secondary outcomes were time to first relapse, MRI activity at 2 years, identification of risk factors associated with CDP, and serious infection incidence rates (IIRs). Each outcome was studied using an inverse probability of treatment weighting method. The outcomes were modeled using a weighted proportional Cox model for the time-to-event outcomes and by a logistic regression regarding the MRI activity., Results: A total of 1,184 patients (426 treated and 758 untreated) fulfilled the inclusion criteria. Median age (Q1-Q3) was 56 years (49.3-63.8), and 52.7% were female. Among treated patients, 295 received rituximab, whereas 131 received ocrelizumab. At baseline, anti-CD20-treated patients were younger (median 51.9 vs 58.6 years, Cohen d = 0.683) and had more active disease (54.5 vs 27.8%, Cohen d = 0.562). 91.6% were drug-naive at inclusion. In time to first CDP analysis, no statistical significance was observed (hazard ratio [HR], 1.13; 95% CI 0.93-1.36, p = 0.2113). In time to first relapse analysis, a nonsignificant trend toward fewer patients relapsing in the treated group was observed (HR 0.83; 95% CI 0.48-1.28, p = 0.0809). For MRI activity, no significant difference was found between the 2 groups. Risk factors associated with CDP in the treated group were male sex and MS duration. IIR was 6.67 (95% CI 3.12-14.25) per 100 person-years in the treated group vs 2.67 (95% CI 0.80-8.86) in the untreated group., Discussion: Time to first CDP was not different between anti-CD20 treated and untreated patients with PPMS. Although our study is retrospective and mainly included patients treated by rituximab, our results indicate that there should be a constant evaluation of all available data to ascertain the best risk/benefit ratio for patients with PPMS., Classification of Evidence: This study provides Class III evidence that anti-CD20 therapy of previously untreated patients with PPMS was not superior to no therapy in delaying time to first CDP.

Background: Congenital diaphragmatic hernia (CDH) is a rare disease that affects the development of the diaphragm, leading to abnormal lung development. Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage., Methods: We have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4 Cre ;Wt1 fl/fl CDH genetic mice model. Morphometric and histological studies were carried out. Immune cell infiltration was assayed by immunochemistry and immunofluorescence and retinoic pathway gene expression analyzed in vivo and in vitro in macrophages., Results: We found that administering a single dose of atypical TLR2/4 ligands (CS1 or CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4 Cre ;Wt1 fl/fl CDH genetic mice model. Only 1 out of 11 mutant embryos showed CDH after CS1 administration, whereas CDH prevalence was 70% in untreated mutant embryos. Mechanistically, CS1 stimulated the infiltration of repairing M2 macrophages (CD206 + and Arg1 + ) into the damaged diaphragm and reduced T cell infiltration. Additionally, those TLR ligands induced retinol pathway genes, including RBP1, RALDH2, RARα, and RARβ, in the affected lungs and the diaphragm and in macrophages in vitro., Conclusions: Our research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment., (© 2024. The Author(s).)

Background: We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of fatigue and their association with physical disability following start of disease-modifying therapy (DMT)., Methods: Using a group-modelling approach, we assessed trajectories of fatigue with the Fatigue Scale for Motor and Cognitive Functions and physical disability with Expanded Disability Status Scale among 1587 and 1818 individuals who initiated a first DMT and had a first DMT switch, respectively, followed during 2011-2022. We investigated predictors of fatigue trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories., Results: We identified five trajectories of fatigue in participants who initiated their first DMT: no fatigue (mean starting values=23.7; 18.2% of population), low (35.5; 23.9%), mild (49.0; 21.6%), moderate (61.3; 20.1%) and severe (78.7; 16.1%). While no, low, mild and severe fatigue trajectories remained stable, the moderate trajectory increased to severe fatigue. Similarly, we identified six fatigue trajectories among participants who did a DMT switch, all indicating stable values over time. Women initiating a first DMT were more likely than men to display a severe fatigue trajectory, relative to the no fatigue one. There was a strong association between fatigue and physical disability trajectories., Conclusions: In this cohort of people with actively treated RRMS, self-reported fatigue remained stable or increased over the years following DMT start. There was a strong association between fatigue and disability after DMT start., Competing Interests: Competing interests: KG, YQ and AH are employees at Janssen Pharmaceuticals, Johnson and Johnson. FP has received research grants from Janssen, Merck KGaA and UCB, and fees for serving on DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of expert witness statement for Novartis., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Cerebral venous sinus thrombosis has not been reported in anti-N-methyl-D-aspartate receptor-antibody encephalitis in the absence of an underlying thrombotic state while rituximab induced cerebral venous sinus thrombosis is rarely reported. We report a patient with anti-N-methyl-D-aspartate receptor-antibody encephalitis without a prothrombotic state who developed cerebral venous sinus thrombosis following rituximab treatment., Case Presentation: A 15-year-old Sri Lankan girl who had been in remission following an episode of anti-N-methyl-D-aspartate receptor-antibody encephalitis 2 years ago, presented with a relapse of anti-N-methyl-D-aspartate receptor-antibody encephalitis characterized by recurrent seizures, mutism, and cognitive abnormalities. Since response was inadequate to first-line immunotherapy, she was administered four doses of rituximab at weekly intervals. Two days after the fourth dose, she developed increasing headaches, and her cranial magnetic resonance venogram confirmed the development of cerebral venous sinus thrombosis. Screening for prothrombotic states were negative. She made an unremarkable recovery following anticoagulation., Conclusion: This case highlights the occurrence of the rare but serious complication of cerebral venous sinus thrombosis following rituximab in the context of anti-N-methyl-D-aspartate receptor-antibody encephalitis and informs the clinician to be wary of new onset headache in patients with anti-N-methyl-D-aspartate receptor-antibody encephalitis treated with immunotherapy., (© 2024. The Author(s).)

Background: Progressive multifocal leukoencephalopathy (PML) is an often fatal disease of the central nervous system caused by opportunistic infection of John Cunningham Polyomavirus (JCV). There's still no antiviral therapeutic strategy which was generally recognized as effective. The prognosis may differ in patients with different pathological mechanisms and treatments. We aim to report the effectiveness of combined treatment of low-dose, long-term immunoglobulin and mirtazapine in a pathologically proved PML case., Case Presentation: A patient presented with progressive acalculia, right-left confusion and visual neglection was recorded. She received 10-year immunosuppressive therapy for dermatomyositis. White matter lesions located in bilateral parietal lobe and callosum area symmetrically in MR scanning. JC virus analysis and brain biopsy in left parietal lobe were performed. The number of JCV copies was 2595 in CSF and 282,809 in brain specimen. Abundant foamy macrophages and the lymphatic cells were obvious in immunohistochemistry staining. Few SV-40 positive JC infected cell and more CD4 + and CD68 + cells were predominant. Immunosuppressive drugs were terminated after being diagnosed as PML for positive JCV and pathological characteristics. In addition, immunoglobulin (5 g/day) and mirtazapine (45 mg/day) were used. JC virus in CSF decreased to 0 after treatment for 4 months and was still negative in June 2023. The clinical symptoms improved, and white matter lesions recovered significantly., Conclusions: We demonstrated that the combination treatment of IVIG and mirtazapine was effective in PML. Low-dose, long-term immunoglobulin might regulate the immune status in our case with controlled inflammatory reaction instead of destructive virus spreading. The therapy may be a prospective option for PML., (© 2024. The Author(s).)

Background: Brain volume loss (BVL) has been identified as a predictor of disability progression in relapsing multiple sclerosis (RMS). As many available disease-modifying treatments (DMTs) have shown an effect on slowing BVL, this is becoming an emerging clinical endpoint in RMS clinical trials., Methods: In this study, a systematic literature review was conducted to identify BVL results from randomized controlled trials of DMTs in RMS. Indirect treatment comparisons (ITCs) were conducted to estimate the relative efficacy of DMTs on BVL using two approaches: a model-based meta-analysis (MBMA) with adjustment for measurement timepoint and DMT dosage, and a network meta-analysis (NMA)., Results: In the MBMA, DMTs associated with significantly reduced BVL versus placebo at two years included fingolimod (mean difference [MD] = 0.25; 95% confidence interval [CI] = 0.15 - 0.36), ozanimod (MD = 0.26; 95% CI = 0.12 - 0.41), teriflunomide (MD = 0.38; 95% CI = 0.20 - 0.55), alemtuzumab (MD = 0.38; 95% CI = 0.10 - 0.67) and ponesimod (MD = 0.71; 95% CI = 0.48 - 0.95), whereas interferons and natalizumab performed the most poorly. The results of NMA analysis were generally comparable with those of the MBMA., Conclusions: Limitations of these analyses included the potential for confounding due to pseudoatrophy, and a lack of long-term clinical data for BVL. Our findings suggest that important differences in BVL may exist between DMTs. Continued investigation of BVL in studies of RMS is important to complement traditional disability endpoints, and to foster a better understanding of the mechanisms by which DMTs can slow BVL., (© 2024. The Author(s).)

Nutrition may affect animal health due to the strong link between them. Also, diets improve the healing process in various disease states. Cancer is a disease, where the harmful consequences of tumors severely impair the body. The information regarding the evolution of this disease is extrapolated from human to animal because there are few specific studies regarding nutritional needs in animals with cancer. Thus, this paper aims to review the literature regarding the immunomodulatory effects of vitamins in mammal cancer. An adequate understanding of the metabolism and requirements of nutrients for mammals is essential to ensuring their optimal growth, development, and health, regardless of their food sources. According to these: 1) Some species are highly dependent on vitamin D from food, so special attention must be paid to this aspect. Calcitriol/VDR signaling can activate pro-apoptotic proteins and suppress anti-apoptotic ones. 2) Nitric oxide (NO) production is modulated by vitamin E through inhibiting transcription nuclear factor kappa B (NF-κB) activation. 3) Thiamine supplementation could be responsible for the stimulation of tumor cell proliferation, survival, and resistance to chemotherapy. 4) Also, it was found that the treatment with NO-Cbl in dogs is a viable anti-cancer therapy that capitalizes on the tumor-specific properties of the vitamin B12 receptor. Therefore, diets should contain the appropriate class of compounds in adequate proportions. Also, the limitations of this paper are that some vitamins are intensively studied and at the same time regarding others, there is a lack of information, especially in animals. Therefore, some subsections are longer and more heavily debated than others., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Munteanu, Mârza and Papuc.)

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare, predominantly drug-induced, acute, life-threatening diseases of skin and mucosae. SJS and TEN are nowadays considered variants of one disease entity with varying degrees of severity called epidermal necrolysis (EN). EN is associated with high morbidity and mortality and constitutes a major disease burden for affected patients. The guideline "Diagnosis and treatment of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis)" was developed under systematic consideration of existing scientific literature and in a formal consensus process according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF) to establish an evidence-based framework to support clinical decision-making. The interdisciplinary guideline commission consisted of representatives from various specialist societies and patient representatives. The guideline is aimed at specialists in the fields of dermatology, ophthalmology, plastic surgery, intensive care, and pediatrics in hospitals and offices, as well as other medical speciallved in the diagnosis and treatment of EN. The guideline is also aimed at patients, their relatives, insurance funds, and policymakers. This first part focuses on the diagnostic aspects, the initial management as well as the immunomodulating systemic therapy., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Differences in the MS course between White and Black populations is well accepted. The existence of a large Somali immigrant population in Minnesota facilitates a study of MS characteristics in this immigrant native African population. The objective of this study was to compare Somali American (SA), African American (AA), and White American (WA) persons with MS (pwMS) regarding clinical features and disease modifying therapy (DMT) use., Methods: This single center (Mayo Clinic) geographically-restricted retrospective cohort study (residing within 250 miles of Rochester, MN, USA) included participants seen before May 2023. Age at immigration to the USA; age at MS onset; DMT use/type; MS phase/phenotype; age at progressive MS (PMS) onset; and proportion with severe MS (expanded disability status scale-EDSS ≥6) were examined., Results: 18 SApwMS, 92 AApwMS, and 94 WApwMS were included. Of the 15 SApwMS not born in USA, 3/15 immigrated pre-puberty, 3/15 peri‑puberty, 8/15 post-puberty, and 1/15 at an unknown date. SApwMS were younger at MS onset (median years, interquartile range (IQR)=25, 22-33 vs. AApwMS: 31, 25-38; p = 0.049 vs. WApwMS: 35, 27-41; p = 0.022). DMT use frequencies were 13/19 SApwMS, 69/92 AApwMS, 80/94 WApwMS (p > 0.05). SApwMS were treated with DMT earlier than AApwMS (HR 2.16, p = 0.012) and WApwMS (HR 1.86, p = 0.041). SApwMS were less commonly treated with natalizumab (SApwMS 0 %, AApwMS 13 %, WApwMS 25 %; p = 0.035) and anti-CD20 therapies (SApwMS 23 %, AApwMS 23 %, WApwMS 48 %; p = 0.005). PMS occurred in 3/19 SApwMS, 28/92 AApwMS and 29/94 WApwMS (p > 0.05). Age of PMS onset in SApwMS (47 years, 34-57) was similar to WApwMS (47 years, 31-71; p > 0.05) but older than AApwMS (41 years, 18-7; p = 0.008)., Conclusions: SApwMS that recently immigrated to the USA have similar disease course to WApwMS, and better than AApwMS from the same geographical region., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

The purpose of this study is to determine whether adding intravenous methylprednisolone pulse (IVMP) to primary adjunctive prednisolone with intravenous immunoglobulin (IVIG) improves treatment resistance and coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) with a high risk of treatment resistance. This multicenter, prospective, observational study was conducted at 28 hospitals in Japan from October 2016 to June 2020. For patients predicted to be resistant to treatment based on a Kobayashi score ≥ 5 and total bilirubin ≥ 1.0 mg/dL, each hospital independently decided to add IVMP followed by prednisolone, prednisolone alone, or nothing to the primary IVIG therapy. In total, 2856 consecutive KD patients were enrolled; of these, 399 (14.0%) were predicted to be treatment resistant. Patients who were resistant to the primary treatment and required additional treatment comprised 59%, 20%, and 26% of the IVIG-alone group, IVIG-plus-prednisolone group, and IVIG-plus-IVMP group, respectively (P < .0001). The CAA incidence (Z score ≥ 2.5) at month 1 was similar among the treatment groups (6.7%, 4.8%, and 7.3%, respectively; P = .66). CAA occurred more frequently in patients who needed third- or later-line therapy.Conclusions: Primary adjunctive corticosteroid therapy improved the treatment response and suppressed inflammation. However, the study found no benefit of adding IVMP to prednisolone therapy. Patients receiving IVIG alone achieved coronary outcomes comparable to those of patients receiving primary adjunctive corticosteroid therapy although they were more likely to require additional rescue treatment. KD inflammation should be resolved no later than the third line of additional treatment to reduce the risk of CAA.Trial registration: University Hospital Medical Information Network Clinical Trials Registry in Japan ( https://www.umin.ac.jp/ctr/index.htm ) under code UMIN000024937., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose of Review: The development and use of immunomodulators and other therapies during the coronavirus disease 2019 (COVID-19) pandemic provided several lessons with respect to these therapies, and to how medical researchers and clinicians should approach the next pandemic., Recent Findings: New or repurposed therapies, particularly immunomodulator treatments, for the treatment of an infectious disease will always be associated with inherent patient risk and this was the case during the COVID-19 pandemic. The concomitant development and use of effective antimicrobial therapies along with close monitoring for secondary infections is paramount for patient safety and treatment success. The development of immunomodulators and other therapies during the COVID-19 pandemic further highlighted the importance of maintaining high standards for medical research for all potential treatment with large double-blind placebo-controlled trials and peer review being the best mode of disseminating medical results rather than social media outlets., Summary: The next new and emerging pandemic will undoubtedly share many of the same challenges posed by COVID-19. It is important that researchers and clinicians learn from this experience, adhere to tried and true clinical care, all the while conducting high quality research aimed at developing definitive treatments., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Systemic sclerosis (SSc) is a heterogenous, multi-system autoimmune disease that causes progressive fibrosis of the skin and internal organs, resulting in high morbidity and mortality. Intravenous Immunoglobulin (IVIG) is a therapeutic option for SSc; however, reports of its efficacy have been variable, and its use across multiple organ manifestations of SSc has not been comprehensively reviewed., Aim: The aim of this study was to systematically assess the existing literature on the role of IVIG use across a range of SSc manifestations., Methods: Medline, Embase, Cochrane, Web of Science and Scopus were searched from 01/01/2003-15/04/2024 using terms related to SSc and IVIG. Included studies were English-language full texts, where ≥5 adults with SSc received IVIG, and where a reportable outcome was documented., Results: Of 418 potentially relevant records, 12 were included in this review, comprising 266 patients across one randomised control trial, two pilot studies, one open label study, seven retrospective studies and one case control study. Eighteen outcomes were documented across five different organ systems: cutaneous, respiratory, musculoskeletal, gastrointestinal, and other (clinical improvement and corticosteroid sparing benefit). Results showed a favourable effect of IVIG in reducing the extent of skin thickening, muscle and joint pain, gastrointestinal symptoms, steroid dosing and improving patient/physician reported quality of life. Whilst IVIG may appear to be less beneficial for respiratory disease, the stabilisation in pulmonary function tests and radiological features may be considered a positive outcome in itself. Limitations included a lack of high-quality studies, and the use of concomitant therapies in many studies, rendering the efficacy of IVIG alone difficult to ascertain., Conclusion: IVIG showed benefit in treating some manifestations of SSc, however there was a lack of convincing evidence for the efficacy in others. The lack of high-quality data highlights the need for further well-designed clinical trials to confirm these findings and inform guidelines for IVIG use., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Messenger RNA (mRNA) vaccines have made remarkable public health contributions during the pandemic and initiated a new era for nucleic acid-based therapeutics. With the unique strength of nucleic acids, including not only mRNA but also DNA, microRNA, small interfering RNA (siRNA), and other nucleic acids, either in tuning off genes or introducing function, nucleic acid therapeutics have been regarded as potential candidates for the treatment of many different diseases, especially for the immunomodulation in cancer. However, the scope of the applications was limited by the challenges in delivery due to intrinsic properties of nucleic acids including low stability, immunogenicity, and toxicity. Bioengineering approaches toward efficient and targeted delivery of therapeutic nucleic acids have gained momentum in clinical applications in the past few decades. Recent advances in the biotechnological approaches for the delivery of mRNA, siRNA, and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas for immunomodulatory are promising alternatives in designing future cancer immunotherapy., Competing Interests: Declaration of Competing Interest Li Tang is a co-founder, shareholder, and advisor for Leman Biotech. The interests of Li Tang were reviewed and managed by EPFL. The remaining authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Combination therapy consists of both anti-tumor necrosis factor (anti-TNF) and an immunomodulator (IMM) and has been shown to improve outcomes in patients with inflammatory bowel disease (IBD). This study assesses the impacts of IMM withdrawal from combination therapy to anti-TNF monotherapy in children with IBD., Methods: This single-center retrospective cohort study included children with IBD initiated on combination therapy between 2014 and 2019 who discontinued the IMM. We evaluated whether IMM withdrawal impacts laboratory values and disease activity. Linear mixed effects models with random intercepts were used to compare differences between groups. Chi-square and Kruskal-Wallis tests were used for comparisons between patients who did and did not require subsequent escalation of therapy., Results: One hundred and fifty-two patients discontinued the IMM which did not significantly affect disease activity. However, 18% of patients escalated therapy after IMM withdrawal, primarily due to low anti-TNF levels. Lower anti-TNF and higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels before IMM withdrawal were associated with subsequent escalation of therapy. Overall, there was no statistically significant effect on anti-TNF drug levels. Patients with Crohn's disease (CD) on infliximab (IFX) and methotrexate (MTX) who discontinued the IMM had an increase in mean ESR and CRP (p < 0.05)., Conclusions: IMM withdrawal from anti-TNF combination therapy may be considered safe in the setting of higher anti-TNF levels and normal serum inflammatory markers. Clinicians should consider assessing anti-TNF levels and inflammatory markers after IMM withdrawal, especially in patients with CD receiving IFX who discontinued MTX., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AHA) is a rare but severe disease of infancy defined by an acute liver injury, histologically characterized by a widespread giant cell transformation and by an autoimmune hemolysis. GCH-AHA is thought to be immune-mediated being however a distinct entity from juvenile autoimmune hepatitis. In particular, GCH-AHA displays a less favorable response to conventional immunosuppressive treatment compared to classical juvenile autoimmune hepatitis, carrying a higher risk of mortality. In fact, since his first description, conventional therapy with prednisone with azathioprine has been used as first line treatment, however with frequent relapses during tapering, as well as severe side effects related to its prolonged use at high doses in early age. Due to the frequent occurrence of relapse, several immunosuppressive drugs have been tried as second line therapy with doubtful success. In case of severe liver dysfunction and/or severe anemia, transitory remission has been achieved with intravenous immunoglobulins administration, however with temporary response. B-cell depletion treatment, mostly with chimeric anti-CD20 monoclonal antibody (rituximab; RTX) has been used since 2004 with encouraging results mostly in refractory cases as second-line therapy. In this issue, the report of a series of 20 children with GCH-AHA from Shanghai, China, confirms the previous treatment experiences of a greater efficacy in obtaining complete remission of RTX or RTX treatment regimens compared to conventional regimens, with a good safety. To date, published experience with this rare disease suggests that RTX should be considered the cornerstone of treatment for complicated or relapsing cases of GCH-AHA and given the increasing evidence on its efficacy and safety, RTX might be even an acceptable option as first line therapy beside conventional treatment, to drastically reduce the cumulative steroids exposure and its side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Purpose: The index review aims to provide an update on the role of corticosteroids and steroid-sparing immunomodulatory therapy (IMT) in managing patients with infectious uveitis., Method: Narrative literature review., Results: Corticosteroids and immunomodulatory therapy (IMT) focus on the host defense system instead of the pathogen, adjusting exaggerated inflammatory reactions to reduce potential harm to ocular tissues. Systemic or local corticosteroids are primarily selected as adjunctive medication for infectious uveitis. Concomitant corticosteroids have also been used in cases of paradoxical worsening in ocular tuberculosis and immune recovery uveitis in cytomegalovirus (CMV) retinitis. While there is no well-established evidence to support the use of IMT in infectious uveitis, it is occasionally used in clinical settings to treat persistent inflammation following resolution of infection such as cases of ocular tuberculosis and ocular syphilis where an insufficient response is observed with corticosteroids., Conclusion: There is no consensus on the position of immunomodulatory therapy in the management of infectious uveitis with different etiologies. The index review provides an overview of available adjunctive corticosteroids and IMT options to assist clinicians in managing such disease entities more efficiently.

The adverse effects of traditional pharmaceutical immunosuppressive regimens have been a major obstacle to successful allograft survival in vascularized composite tissue allotransplantation (VCA) cases. Consequently, there is a pressing need to explore alternative approaches to reduce reliance on conventional immunotherapy. Cell therapy, encompassing immune-cell-based and stem-cell-based regimens, has emerged as a promising avenue of research. Immune cells can be categorized into two main systems: innate immunity and adaptive immunity. Innate immunity comprises tolerogenic dendritic cells, regulatory macrophages, and invariant natural killer T cells, while adaptive immunity includes T regulatory cells and B regulatory cells. Investigations are currently underway to assess the potential of these immune cell populations in inducing immune tolerance. Furthermore, mixed chimerism therapy, involving the transplantation of hematopoietic stem and progenitor cells and mesenchymal stem cells (MSC), shows promise in promoting allograft tolerance. Additionally, extracellular vesicles (EVs) derived from MSCs offer a novel avenue for extending allograft survival. This review provides a comprehensive summary of cutting-edge research on immune cell therapies, mixed chimerism therapies, and MSCs-derived EVs in the context of VCAs. Findings from preclinical and clinical studies demonstrate the tremendous potential of these alternative therapies in optimizing allograft survival in VCAs., Competing Interests: Declaration of competing interest None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Background: There is a lack information regarding risk factors associated with worse COVID-19 outcomes in patients with multiple sclerosis (MS) in the MENA region., Methods: This is a multicenter, retrospective cohort study that included all MS patients with a suspected or confirmed COVID-19 infection using the MENACTRIMS registry. The association of demographics, disease characteristics, and use of disease-modifying therapies (DMTs) with outcomes and severity of COVID-19 were evaluated by multivariate logistic model., Results: A total of 600 MS patients with confirmed (n = 542) or highly suspected (n = 58) COVID-19 were analyzed. Seventy-three patients (12.2 %) had a COVID-19 severity score of ≥3 on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death] with a cutoff at 3 [hospitalized and not requiring supplemental oxygen]), and 15 patients (2.5 %) died. Out of 73 patients with a severity score ≥3, 90.4 % were on DMTs; 50.6 % of them were on anti-CD20, including ocrelizumab and rituximab. Multivariate logistic regression showed that older age (odds ratio per 10 years, 1.4 [95 %CI, 1.0-1.8]), disability (OR for EDSS 3.0-5.5, 2.9 [95 %CI. 1.5-5.7], OR for EDSS ≥6.0, 2.3 [95 %CI. 1.0-5.1]), obesity (OR, 3.0 [95 %CI, 1.5-6.0]), and treatment with rituximab (OR, 9.0 [95 %CI, 3.1-25.3]) or off-label immunosuppressive medications (OR, 5.6 [95 %CI. 1.1-27.8]) were risk factors for moderate or severe COVID-19., Conclusion: In this registry-based study of MS patients, age, sex, EDSS, obesity, progressive MS were risk factors for severe COVID-19. Moreover, there was an association found between exposure to anti-CD20 DMTs and COVID-19 severity., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: This study aims to explore the treatment pattern of systemic lupus erythematosus (SLE) in Aotearoa/New Zealand., Methods: SLE patients were linked to the pharmaceutical dispensing data. The use of publicly funded anti-malarials, immunomodulators, biologics, glucocorticoids and bisphosphonates were compared by gender, ethnicity, age group, socioeconomic status and year of SLE identification. Adherence to hydroxychloroquine was examined using the medication possession ratio (MPR), with a MPR of ≥0.8 considered as high adherence., Results: Of the 2631 SLE patients, 73.8% used hydroxychloroquine, 64.1% used immunomodulators/biologics and 68.0% used 5 mg or more prednisone daily for at least 90 days. Women were more likely to use hydroxychloroquine than men. Asian patients had a different treatment pattern than other ethnic groups, and Māori were less likely to use hydroxychloroquine. The proportions of patients using different treatments decreased with age. Of the patients using hydroxychloroquine, 54.5% had high adherence. For patients over 40 years old and on long term prednisone, 47.3% had bisphosphonates and this figure was 17.8% for patients under the age of 40 years old. Patients with better socioeconomic status had a higher probability of using bisphosphonates than patients with lower socioeconomic status., Conclusions: Adherence to hydroxychloroquine in these patients varied and was lower in men and in Māori. Prednisone is commonly prescribed and used long term. Half of those over the age of 40 years old co-administered bisphosphonate. Further research is needed to identify the reasons for these discrepancies on SLE treatments by gender, ethnicity, age and socioeconomic status., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The objective of this study was to ascertain pegloticase persistence and adverse events associated with concomitant immunomodulatory drug treatment in patients with gout., Methods: We conducted a retrospective analysis of patients with gout using the American College of Rheumatology's Rheumatology Informatics System for Effectiveness registry from January 2016 through June 2020. The first pegloticase infusion defined the index date. Based on concomitant immunomodulatory drug treatment, we identified three exposure groups: (1) immunomodulatory drug initiators (patients initiating an immunomodulatory prescription ±60 days from the index date), (2) prevalent immunomodulatory drug recipients (patients receiving their first immunomodulatory drug prescription >60 days before the index date with at least one prescription within ±60 days of the index date), and (3) immunomodulatory nonrecipients (patients receiving pegloticase without concomitant immunomodulatory drugs). We calculated the proportion of patients who achieved serum urate levels ≤6 mg/dL and who had laboratory abnormalities (white blood cell count <3.4 x 10 9 /L, platelet count <135,000, hematocrit level <30%, alanine aminotransferase or aspartate aminotransferase level ≥1.5 times the upper limit normal value) within 180 days after the index date. Cox regression analyzed time to pegloticase discontinuation, controlling for potential confounders., Results: We identified 700 pegloticase recipients (91 immunomodulatory drug initiators, 33 prevalent immunomodulatory drug recipients, and 576 nonrecipients), with a median follow-up of 14 months. Immunomodulatory drug recipients were less likely to discontinue pegloticase. The adjusted hazard ratios of pegloticase discontinuation associated with concomitant immunomodulatory drug initiation and prevalent treatment were 0.52 (95% confidence interval [CI] 0.37-0.75) and 0.69 (95% CI 0.42-1.16), respectively. Laboratory abnormalities were uncommon (<5%) and were not higher in concomitant immunomodulatory drug treatment., Conclusion: Consistent with clinical trials, results from this large observational registry suggest that concomitant immunomodulatory drug treatment improves pegloticase persistence., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and -extrinsic factors during tumor progression is critical for developing new therapeutic strategies., (Published by Elsevier Inc.)

Kawasaki disease (KD), which is also known as cutaneous mucosal lymph node syndrome, is an acute, self-limiting, necrotizing vasculitis with unclear cause that primarily affects small- and medium-sized blood vessels and most commonly affects children aged 6 months to 5 years. Currently, diagnosis is based primarily on typical clinical symptoms. Approximately 15%-20% of patients are highly suspected of having KD; however, they do not match the diagnostic criteria for typical KD, which is referred to as incomplete Kawasaki disease (IKD), and this has become a major challenge in the diagnosis and treatment of KD. We describe a case of a 7-year-old boy who had a fever and jaundice as his initial symptoms. After a series of clinical laboratory and imaging examinations and marked improvement of symptoms after treatment with intravenous immunoglobulin (IVIG), IKD was considered as the diagnosis. When children present with jaundice and fever, physicians should consider KD as a possible diagnosis to ensure early detection and treatment of the disease.

Background: This study aimed to evaluate the effectiveness of Egami, Kobayashi and Sano scores in predicting intravenous immunoglobulin (IVIG) resistance in infant Kawasaki disease (KD), considering its unique clinical presentation., Methods: We retrospectively analysed 143 infants aged < 12 months and diagnosed with KD at a single centre from 2019 to 2023. Patients were divided into IVIG-resistant and IVIG-responsive groups. Demographic, clinical and laboratory data were compared between the groups. The diagnostic performance of Egami, Kobayashi and Sano scores in predicting IVIG resistance was evaluated using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUC). Additionally, we developed a new scoring system based on significant predictors identified in our cohort., Results: Among 143 infants, 45 (31.5%) showed IVIG resistance. The IVIG-resistant group had a significantly higher rate of coronary artery lesions (15.6% vs. 5.1%, p = 0.036). Incomplete KD was observed in 61.5% of cases. Egami, Kobayashi and Sano scores exhibited low sensitivity (35.6%, 55.6% and 20%, respectively) and moderate specificity (77.6%, 63.3% and 95.9%, respectively) in predicting IVIG resistance. The AUC ranged from 0.583 to 0.674, indicating poor to fair discriminative ability. Our newly developed scoring system, based on total bilirubin and albumin levels, showed similar performance (AUC 0.633) to existing scores., Conclusions: Existing Japanese risk scoring systems and our newly developed score showed limited effectiveness in predicting IVIG resistance in infant KD. The high proportion of incomplete presentation and IVIG resistance in infants highlights the need for age-specific risk assessment and management. Further research is necessary to develop more sophisticated, dedicated prediction model for IVIG resistance in infants with KD., (© 2024. The Author(s).)

Background: Immunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans., Methods: Sri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database., Results: SLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7-65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C9*3 (rs1057910) and NUD15*3 (rs116855232), with MAFs of 35.3% (32.7-37.9), 12.2% (10.4-13.9), 10.9% (9.2-12.6), 9.8% (8.2-11.4), 8.3% (6.8-9.8) respectively. Less commonly present variants included CYP2C9*2 (rs1799853) (2.5%[1.7-3.4]), TPMT*3C (rs1142345) (1.9%[1.1-2.6]), TPMT*3B (rs1800460) (0.2%[0-0.5]), CYP3A5*6 (rs10264272) (0.2%[0-0.4]) and CYP3A4*18 (rs28371759) (0.1%[0-0.2]). The SLC19A1 (rs1051266), NUD15*3 (rs116855232), CYP2C9*3 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT*3B (rs1800460), and CYP2C9*2 (rs1799853) were significantly less prevalent among Sri Lankans than in  many other populations. Sri Lankans exhibited lower prevalence of TPMT*3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A4*18 (rs28371759) compared to East-Asians; and CYP3A5*6 (rs10264272) compared to African/African-Americans and Latino-Americans., Conclusion: Sri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT*3B, TPMT*3C), reduced tacrolimus efficacy (CYP3A4*18), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A5*6) are less common. This highlights need for targeted medication strategies to improve treatment outcomes., (© 2024. The Author(s).)

A neonate presented to a tertiary clinic with blisters and erosions over his trunk and extremities. The mother had multiple erosions with crusts affecting the scalp, oral cavity and trunk present since the first trimester and worse since delivery. Skin biopsy for histopathology and direct immunofluorescence confirmed pemphigus vulgaris (PV) in the mother. Indirect immunofluorescence assays for serum antibodies against desmogleins 1 and 3 were positive in both mother and baby confirming a diagnosis of neonatal PV. The baby's lesions healed spontaneously within 2 weeks, and the mother was clear at 2 months following treatment with rituximab., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome., Methods: Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses., Results: A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%., Discussion: In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred., Classification of Evidence: This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

Background: Highly active (HA) relapsing remitting multiple sclerosis (RRMS) is associated with frequent relapses and high burden of disease/disability. Natalizumab is licensed for HA RRMS, including rapidly evolving severe (RES) (≥2 relapses in previous year) and sub-optimally treated (SOT) (≥1 relapse in previous year despite treatment) populations. However, there is limited RCT evidence in the SOT subpopulation., Objective: To review the non-RCT evidence for natalizumab in SOT HA RRMS., Methods: Databases were searched to January 2023 for non-randomised studies of natalizumab in HA RRMS. Studies in patients with ≥1 relapse during previous treatment were eligible for inclusion. Meta-analyses were conducted to compare natalizumab with platform and higher efficacy disease-modifying therapies, with sensitivity analysis restricted to studies of low risk of bias., Results: Included comparative studies (n = 16) showed natalizumab had lower relapse rates, disease activity and MRI (radiological) outcomes compared with platform and higher efficacy therapy. Case series (n = 11) showed natalizumab was associated with high rates of freedom from relapse and clinical/radiological disease activity and reductions in annualised relapse rate and disability progression., Conclusions: Literature reviewed indicates that natalizumab is more effective than other included treatments for SOT patients. Findings were consistent with studies in the broad HA RRMS population, suggesting that natalizumab may have similar efficacy for SOT and RES HA RRMS., Competing Interests: Declaration of competing interest MC, AS, TA, DW, MA and RM have no conflicts of interests. CG, HD, MT are Biogen Employees and stockholders., (Copyright © 2024. Published by Elsevier B.V.)

Immunotherapy has proved to be a breakthrough in cancer treatment. So far, a bulk of the approved/late-stage cancer immunotherapy are antibody-based. Although these antibody-based drugs have demonstrated great promise, a majority of them are limited due to their access to extracellular targets, lack of oral bioavailability, tumor microenvironment penetration, induction of antibody dependent cytotoxicity etc. In recent times, there has been an increased research focus on the development of small molecule immunomodulators since they have the potential to overcome the aforementioned limitations posed by antibodies. Furthermore, while most biologics based therapeutics that are in clinical use are limited to modulating the adaptive immune system, very few clinically approved therapeutic modalities exist that modulate the innate immune system. The innate immune system, which is the body's first line of defense, has the ability to turn cold tumors hot and synergize strongly with existing adaptive immune modulators. In preclinical studies, small molecule innate immune modulators have demonstrated synergistic efficacy as combination modalities with current standard-of-care immune checkpoint antibodies. In this review, we highlight the recent advances made by small molecule innate immunomodulators in cancer immunotherapy., Competing Interests: AG, SG, PK, KS, BD, and AK are employees of Aten Porus Lifesciences APL. AK is the co-founder of both APL and Avammune Therapeutics USA., (Copyright © 2024 Goswami, Goyal, Khurana, Singh, Deb and Kulkarni.)

The utility of Rituximab (RTX) for IgA vasculitis nephritis (IgAVN) is not well established. Up to now, we analysed the largest samples of IgAVN patients treated by RTX with a total of 41 retrieved subjects up to December 29, 2023 in the present systematic review. We assessed the clinical profiles, efficacy, and safety of RTX treatments. The present review showed that the renal function tended to be stabilized (P = 1.000) and urinalysis tended to normalize after RTX treatment with no serious adverse events reported. Moreover, 40% (16/40) of patients was freed use of glucocorticoid after RTX administration (P < 0.001). The remission rate was 92.7% (38/41) and complete remission rate was 46.3% (19/41) in IgAVN patients. Interestingly, 76.9% (10/13) of IgAVN child patients achieved complete remission when compared with 32.1% (9/28) of adult patients (P = 0.017). In summary, our results support the benefit of RTX therapy in IgAVN patients, especially children subjects., (© 2024. The Author(s).)

Background: Patients with inflammatory bowel disease (IBD) treated with immunomodulators or biologic therapy are at increased risk of infections. Malnutrition and vitamin or mineral deficiencies are common among patients with IBD. The results of various studies have indicate that vitamin deficiencies might increase the risk of infections. To evaluate the efficacy of a multivitamin and mineral supplement on the incidence of infections in patients with IBD treated with immunomodulators, biologic therapy, or combination therapy., Methods: This was a single-center, randomized, double-blind, placebo-controlled clinical trial to compare a multivitamin and mineral supplement (supplemented group) vs identical-in-appearance placebo (placebo group) in a total of 320 non-vitamin-deficient patients with IBD (Crohn's disease or ulcerative colitis) in remission with immunomodulators, biologic therapy, or combination therapy. Participants were asked to take a daily multivitamin and mineral supplement or placebo and report the occurrence of infections during a 24-week period of follow-up., Results: Treatment arms consisted of 162 and 158 patients for the supplement and placebo, respectively. In both treatment groups, 107 patients reported an infection during the 24-week follow-up period (unadjusted odds ratio, 0.93; 95% confidence interval, 0.56-1.48). In the supplemented group, 32 patients received antibiotics for an infection compared with 21 patients in the placebo group (unadjusted odds ratio, 1.61; 95% confidence interval, 0.88-2.93)., Conclusions: An over-the-counter multivitamin and mineral supplement did not reduce the risk of infection for patients with IBD in remission with immunomodulators, biologic therapy, or combination therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The Epstein-Barr virus (EBV) is associated with many malignancies and autoimmune diseases, including multiple sclerosis. In addition, EBV rarely but occasionally causes central nervous system (CNS) complications. We herein report a case of transverse myelitis (TM) associated with systemic EBV reactivation after herpes zoster infection in a cord blood transplant recipient. Identification of EBV-infected peripheral blood cells revealed a predominance of B cells. Notably, intravenous rituximab ameliorated EBV reactivation and TM. Since the CNS infiltration rate of intravenous rituximab is markedly low, the clinical efficacy of rituximab against TM suggests that EBV reactivation may cause TM via immune-mediated mechanisms.

Background: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset., Methods: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use., Results: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)]., Conclusions: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges., (© 2024. The Author(s).)

Purpose: We report the long-term effect of rituximab (RTX) in scleritis and determine the value of B-cell monitoring for the prediction of relapses., Methods: We retrospectively studied 10 patients with scleritis, who were treated with RTX. Clinical characteristics were collected, and blood B-cell counts were measured before the start of RTX, and at various time points after treatment., Results: Clinical activity of scleritis decreased after RTX treatment in all patients within a median time of 8 weeks (range 3-13), and all reached remission. The median follow-up was 101 months (range 9-138). Relapses occurred in 6 out of 10 patients. All relapses, where B-cell counts were measured (11 out of 19), were heralded by returning B cells. However, B cells also returned in patients with long-term remissions., Conclusions: RTX is a promising therapeutic option for scleritis. Recurrence of B cells after initial depletion does not always predict relapse of scleritis.

Background: Dupilumab effectively treats atopic dermatitis (AD); however, its role in halting the atopic march remains uncertain., Objective: To investigate dupilumab's effect on atopic march in pediatric AD patients versus conventional immunomodulators., Methods: This retrospective cohort study utilized data from the TriNetX US Collaborative Network (2011-2024). Pediatric AD patients (≤18 years) were categorized into DUPI-cohort (newly prescribed dupilumab) or CONV-cohort (prescribed conventional immunomodulators without dupilumab). After 1:1 propensity-score matching, we analyzed atopic march progression, defined by the incident asthma or allergic rhinitis (AR). Cumulative incidence was plotted using Kaplan-Meier, with risk assessment via Cox regression., Results: The study included 2192 patients in each cohort. The 3-year cumulative incidence of atopic march progression was lower in the DUPI-cohort than the CONV-cohort (20.09% vs 27.22%; P < .001). The DUPI-cohort demonstrated significant risk reduction in atopic march progression (hazard ratio [HR] 0.68, 95% CI 0.55-0.83), individual asthma (HR 0.60, 0.45-0.81), and individual AR (HR 0.69, 0.54-0.88). Younger patients on dupilumab exhibited a greater risk reduction for atopic march progression and individual asthma, contrasting with the opposite age-related pattern for individual AR., Limitations: Observational study., Conclusion: Among pediatric AD patients, dupilumab was associated with reduced risk of atopic march progression compared with conventional therapies., Competing Interests: Conflicts of interest None declared., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Histologic evaluation of mucosal healing in Crohn's disease is an evolving treatment target. We evaluated histologic outcomes for mirikizumab efficacy and associations with endoscopic and 1-year outcomes., Methods: Biopsy specimens from 1 ileal and 4 colonic segments were evaluated at weeks 0, 12, and 52 from each of the 170 SERENITY participants. Criteria for the weeks 12 and 52 histologic response were no epithelial neutrophils or epithelial damage, or >50% decrease in either the Robarts Histopathology Index or the active Global Histologic Disease Activity Score, and remission (no mucosal neutrophils and no epithelial damage) had to be met in all biopsy specimens. Agreement was evaluated between histologic and endoscopic end points. Associations between 1-year outcomes and week 12 histologic and endoscopic response were evaluated., Results: At week 12, 1000 mg mirikizumab resulted in greater rates of histologic response (66% vs 27%; P < .001) and remission (26% vs 6%; P < .01) than placebo. Rates were numerically similar at 1 year (mirikizumab pooled response, 46%-69%; remission, 13%-31%). Agreement between week 12 histologic and endoscopic response was 69% (Cohen's kappa coefficient [κ] = 0.40) and remission was 83% (κ = 0.38) in all pooled arms, including placebo. At 1 year, the percentage of participants who received any dose of mirikizumab and achieved endoscopic remission differed by their week 12 response: histologic (20%), endoscopic (25%), combined histology-endoscopy (45%), or neither (4%) (P = .003)., Conclusions: In a post hoc analysis of phase 2 data, mirikizumab induced and sustained histologic response and remission in Crohn's disease over 52 weeks. Early combined histologic-endoscopic response was associated with endoscopic remission after 1 year of treatment with mirikizumab (ClinicalTrials.gov NCT02891226)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: Oral squamous cell carcinoma (OSCC) presents a significant health challenge, requiring effective treatments. Magnolol, a compound with potential anticancer properties, warrants investigation in OSCC treatment. Here, we aimed to assess the efficacy of magnolol in inhibiting progression of OSCC and to explore the underlying mechanisms of its action., Materials and Methods: We evaluated the effect of magnolol on tumor progression using the MOC1-bearing orthotopic model. We examined its impact on pathology and toxicity through hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and biochemical analysis. We also investigated the immunoregulatory effects of magnolol in the MOC1-bearing model using flow cytometry., Results: At high doses, magnolol significantly reduced tumor volume (p<0.0001 for comparisons between treated with magnolol and untreated groups) and weight loss by 70% in vivo. It also induced caspase-dependent apoptosis, evidenced by 2.42-, 2-, and 2.2-fold increases in the expression of caspase-3, -8, and -9, respectively, in mouse tumors treated with high 60 mg/kg of magnolol compared to untreated (p<0.0001 for all comparisons). Magnolol demonstrated no toxicity, maintaining body weight and normal biochemical parameters, including liver and kidney function. Pathological evaluations showed no adverse effects on organs in all treatment groups. Moreover, high doses of magnolol enhanced natural killer cells (by 3%), dendritic cells (20-25%), and cytotoxic T cells (20-40%) while reducing myeloid-derived suppressor cells and regulatory T cells by 1.5 times., Conclusion: Magnolol demonstrates potential as a therapeutic agent for OSCC, offering antitumor efficacy and immunomodulatory benefits., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose of Review: Long-term use of multiple sclerosis (MS) disease-modifying therapies (DMTs) is standard practice to prevent accumulation of disability. Immunosenescence and other age-related changes lead to an altered risk-benefit ratio for older patients on DMTs. This article reviews recent research on the topic of de-escalation and discontinuation of MS DMTs., Recent Findings: Observational and interventional studies have shed light on what happens to patients who de-escalate or discontinue DMTs and the factors, such as age, treatment type, and presence of recent disease activity, that influence outcomes. Though many questions remain, recent findings have been valuable for the development of an evidence-based approach to making de-escalation and discontinuation decisions in MS., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Small series suggest that rituximab could be effective as treatment for autoimmune hepatitis (AIH), although data are scarce. We aimed to evaluate the efficacy and safety of rituximab in different cohorts of patients with AIH., Methods: Multicentre retrospective analysis of the 35 patients with AIH and its variant forms treated with rituximab and included in the ColHai registry between 2015 and 2023., Results: Most patients were female (83%), 10 (29%) had cirrhosis and four (11.4%) variant forms of AIH. Indication for rituximab were as follows: 14(40%) refractory AIH, 19(54%) concomitant autoimmune or haematological disorder, 2(6%) intolerance to prior treatments. In three (9%) subjects with a concomitant disorder, rituximab was the first therapy for AIH. Overall, 31 (89%) patients achieved or maintained complete biochemical response (CBR), including the three in first-line therapy. No difference in CBR was observed according to rituximab indication (refractory AIH 86% vs. concomitant disorders 90%, p = .824) or cirrhosis (80% vs. 92%, p = .319). Rituximab was associated with a significant reduction in corticosteroids (median dose: prior 20 vs. post 5 mg, p < .001) and the discontinuation of ≥1 immunosuppressant in 47% of patients. Flare-free rate at 1st, 2nd and 3rd year was 86%, 73% and 62% respectively. Flares were not associated with the development of liver failure and were successfully managed with repeated doses of rituximab and/or increased corticosteroids. Three (9%) patients experienced infusion-related adverse events (1 anaphylaxis and 2 flu-like symptoms) and five (14%) infections., Conclusion: Rituximab is safe and effective in patients with refractory AIH and those treated due to concomitant autoimmune or haematological disorders., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Delayed radiation myelopathy (DRM) is a rare yet severe complication of radiotherapy. This condition has a progressive pattern that is often irreversible. Several therapeutic strategies have been introduced to alleviate disease complications, including corticosteroids, hyperbaric oxygen, anticoagulants, and antivascular endothelial growth factor (VEGF) agents. However, despite their beneficial effect, they have not been the definitive treatments for DRM. Here we present the case of a 55-year-old woman with a history of multiple myeloma who developed neurological complications 11 months after radiation therapy. As her radiologic findings demonstrated transverse myelitis, based on the DRM diagnostic criteria, the diagnosis of delayed radiation myelitis was reached. Therefore, methylprednisolone pulse therapy was initiated, resulting in the complete resolution of her neurological symptoms. However, on her follow-up examination, although she did not have new neurological complications, magnetic resonance imaging (MRI) demonstrated a residual enhancement in the thoracic spinal cord area. Hence, due to the possibility of myelitis progression and spinal cord atrophy, intravenous immune globulin (IVIG) was administered, resulting in the resolution of lesion enhancement. Considering this outcome and the immunomodulatory properties of IVIG, it could be regarded as a potential therapeutic option in the case of DRM activity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Aims: Multiple sclerosis treatment strategies are changing in the Czech Republic. According to data from 2013-2021, the proportion of patients starting high-efficacy disease-modifying therapies is increasing. In this survey, we describe the actual data trends in multiple sclerosis (MS) patients beginning their first disease‑modifying therapies (DMTs) from 2013 to 2021. The secondary objective was to present the history, data collection, and scientific potential of the Czech National MS registry (ReMuS)., Methods: First, using descriptive statistics, we analysed the data for patients starting their first DMTs, either platform (including dimethyl fumarate) or high-efficacy DMTs (HE-DMTs), for each successive year. Second, a detailed description of the history, data collection, completeness, quality optimising procedures, and legal policies of ReMuS is provided., Results: Based on the dataset from December 31, 2021, the total number of monitored patients with MS in ReMuS increased from 9,019 in 2013 (referred from 7 of 15 MS centres) to 12,940 in 2016 (referred from all 15 Czech MS centres) to 17,478 in 2021. In these years, the percentage of patients treated with DMTs in the registry ranged from 76 to 83%, but the proportion of patients treated with HE-DMTs changed from 16.2% in 2013 to 37.1% in 2021. During the follow-up period, a total of 8,491 treatment-naive patients received DMTs. The proportion of patients (all MS phenotypes) starting HE-DMTs increased from 2.1% in 2013 to 18.5% in 2021., Conclusion: Patient registries, including ReMuS, provide an essential quality data source, especially in light of the increasing percentage of patients on HE-DMTs. Although early initiation of HE-DMT can provide considerable benefits, it also carries greater potential risks. Consistent long-term follow-up of patients in real‑world clinical practice, which only registries allow, is therefore crucial to evaluate the efficacy and safety of therapeutic strategies, for epidemiological research and to assist decision making by healthcare providers and regulatory bodies., Competing Interests: The authors report no conflicts of interest in this work.

Background: Approximately 10-20 % of individuals develop a recrudescent or persistent fever after intravenous immunoglobulin (IVIG) infusion for the initial treatment of Kawasaki disease. The aim of this study was to evaluate the efficacy and safety of the initial IVIG treatment of Kawasaki disease based on duration of infusion., Methods: This retrospective, single-center study included 53 patients with Kawasaki disease who were initially treated with 2 g/kg of IVIG by means of a single infusion from June 2018 to August 2019. We classified patients into two groups based on the duration of the infusion: the 12-h group and the 24-h group. We compared the treatment response of the primary IVIG and its adverse events using the Mann-Whitney U test and Fisher's exact or Chi-square tests., Results: There were no significant differences in the response to initial IVIG treatment between the two groups. The duration from treatment onset to defervescence was shorter in the 12-h group than the 24-h group (7 h vs. 12 h, respectively, p = 0.07); however, this was not significant. There were no significant between-group differences regarding adverse events., Conclusion: We concluded that the initial 12-h IVIG treatment was comparable to the 24-h treatment in terms of efficacy and safety. This will enable physicians to feel confident about pursuing a shorter course of treatment with similar results as conventional treatment and decide on administering additional therapy to their patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. None, (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Resveratrol (RSV), the primary polyphenol found in grapes, has been revealed to have anti-inflammatory properties by reducing the capacity of the peripheral blood mononuclear cells to produce pro-inflammatory cytokines, including IL-1β, IL-6, IL-1ra and TNFα. Considering the close association between chronic inflammation and cancer development, RSV's immunomodulatory properties are one way by which the polyphenol may inhibit cancer initiation, proliferation, neovascularization, and migration. Resveratrol influences the generation of microtumor environment which is one of the key factors in cancer progress. In addition to immunomodulation, RSV inhibits cancer development by expressing anti-oxidant effects, causing cell cycle arrest, stimulating the function of certain enzymes, and activating cell signaling pathways. The end outcome is one of the various forms of cell death, including apoptosis, pyroptosis, necroptosis, and more, as it has been observed in vitro . RSV has been shown to act against cancer in practically every organ, while its effects on colon cancer have been documented more frequently. It is remarkable that longer-term clinical studies that may have established the potential for this natural substance to serve as a therapeutic adjuvant to traditional anti-cancer medications were not prompted by the encouraging outcomes seen with cancer cells treated with non-toxic doses of resveratrol. The current review aims to assess the recent findings about the immunological and anti-cancer characteristics of RSV, with a particular emphasis on cancers of the digestive tract, as a challenge for future clinical research that may contribute to the better prognosis of cancer., Competing Interests: The author declares that they have no conflicts of interest to report regarding the present study., (© 2024 The Author.)

Introduction: Alemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS)., Aim: To evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years., Methods: This prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison., Results: The study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7-42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56-10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1-3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7-52.7] pg/ml and 158.9 [IQR, 126.9-255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03-8.54] pg/ml and 91.0 [72.6-109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values., Conclusion: Alemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values., Competing Interests: RS-A reported receiving research travel support from Roche and Janssen outside the submitted work. EM reported receiving research grants, travel support, or honoraria for speaking engagements from Biogen, Sanofi, Merck, Novartis, Almirall, Roche, Bristol Myers Squibb, and Janssen outside the submitted work. JF reported receiving research travel support from Roche and Janssen outside the submitted work. SM reported receiving personal fees from Almirall, Bristol Myers Squibb, and Teva outside the submitted work and receiving compensation for lectures or travel expenses from Merck Serono, Biogen, Sanofi Genzyme, Roche, Janssen, and Novartis. JC reported receiving personal fees from Sanofi outside the submitted work and receiving speaker honoraria from Biogen Idec and Sanofi. FR reported receiving personal fees from Sanofi outside the submitted work and receiving speaker honoraria from Biogen Idec and Sanofi. LF reported receiving speaker fees and travel support and/or serving on advisory boards for Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Bristol Myers Squibb, Janssen, and Almirall. LV reported receiving grants and personal fees from Merck, Roche, Sanofi Genzyme, Bristol Myers Squibb, Celgene, Biogen, and Novartis outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sainz-Amo, Rodero Romero, Monreal, Chico García, Fernández Velasco, Villarrubia, Veiga González, Sainz de la Maza, Rodríguez Jorge, Masjuan, Costa-Frossard and Villar.)