Spatial transcriptomic brain imaging reveals the effects of immunomodulation therapy on specific regional brain cells in a mouse dementia model.

Increasing evidence of brain-immune crosstalk raises expectations for the efficacy of novel immunotherapies in Alzheimer's disease (AD), but the lack of methods to examine brain tissues makes it difficult to evaluate therapeutics. Here, we investigated the changes in spatial transcriptomic signatures and brain cell types using the 10x Genomics Visium platform in immune-modulated AD models after various treatments. To proceed with an analysis suitable for barcode-based spatial transcriptomics, we first organized a workflow for segmentation of neuroanatomical regions, establishment of appropriate gene combinations, and comprehensive review of altered brain cell signatures. Ultimately, we investigated spatial transcriptomic changes following administration of immunomodulators, NK cell supplements and an anti-CD4 antibody, which ameliorated behavior impairment, and designated brain cells and regions showing probable associations with behavior changes. We provided the customized analytic pipeline into an application named STquantool. Thus, we anticipate that our approach can help researchers interpret the real action of drug candidates by simultaneously investigating the dynamics of all transcripts for the development of novel AD therapeutics.

Network meta-analysis of four common immunomodulatory therapies for the treatment of patients with thin endometrium.

OBEJECTIVE: To compare the effectiveness of endometrial receptivity and pregnancy outcomes of four common immunomodulatory therapies for patients with thin endometrium. METHOD: This systematic review and network meta-analysis using a literature search up to January 2024, to identify relevant trials comparing endometrial receptivity and pregnancy outcomes of human chorionic gonadotropin (hCG), platelet-rich plasma (PRP), infusion of granulocyte colony-stimulating factor (IG-CSF), and peripheral blood mononuclear cell (PBMC) for patients with thin endometrium. We used surface under the cumulative ranking (SUCRA) to ranked four common immunomodulatory therapies on endometrium thickness, implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR). RoB2 and ROBINS-I were used to assess the certainty of evidence. RESULTS: The pooled results of 22 studies showed that hCG (mean difference [MD]: 3.05, 95% confidence interval [CI]: 1.46-4.64) and PRP (MD: 0.98, 95% CI: 0.20-1.76) significantly increase endometrium thickness. The hCG was the best among the IG-CSF (MD = -2.56, 95% CI = -4.30 to -0.82), PBMC (MD = -2.75, 95% CI = -5.49 to -0.01), and PRP (MD = -2.07, 95% CI = -3.84 to -0.30) in increasing endometrium thickness. However, IG-CSF and PRP significantly improved IR (IG-CSF: risk ratio (RR; IG-CSF: RR = 1.33, 95% CI = 1.06-1.67; PRP: RR = 1.63, 95% CI = 1.19-2.23), and LBR (IG-CSF: RR = 1.53, 95% CI = 1.16-2.02; PRP: RR = 1.59, 95% CI = 1.08-2.36). CONCLUSIONS: Available evidence reveals that hCG and subcutaneous or intrauterine CSF (SG-CSF) may be the best treatment options for current thin endometrium patients. However, future high-quality and large-scale studies are necessary to validate our findings.

Suppression of antitumor immune signatures and upregulation of VEGFA as IDH-mutant gliomas progress to higher grade.

OBJECTIVE: Several studies have compared the immune microenvironment of isocitrate dehydrogenase (IDH)-wildtype glioma versus IDH-mutant glioma. The authors sought to determine whether histological tumor progression in a subset of IDH-mutant glioma was associated with concomitant alterations in the intratumoral immune microenvironment. METHODS: The authors performed bulk RNA sequencing on paired and unpaired samples from patients with IDH-mutant glioma who underwent surgery for tumor progression across multiple timepoints. They compared patterns of differential gene expression, overall inflammatory signatures, and transcriptomic measures of relative immune cell proportions. RESULTS: A total of 55 unique IDH-mutant glioma samples were included in the analysis. The authors identified multiple genes associated with progression and higher grade across IDH-mutant oligodendrogliomas and astrocytomas. Compared with lower-grade paired samples, grade 4 IDH-mutant astrocytomas uniquely demonstrated upregulation of VEGFA in addition to counterproductive alterations in inflammatory score reflective of a more hostile immune microenvironment. CONCLUSIONS: Here, the authors have provided a transcriptomic analysis of a progression cohort for IDH-mutant glioma. Compared with lower-grade tumors, grade 4 astrocytomas displayed alterations that may inform the timing of antiangiogenic and immune-based therapy as these tumors progress.

[The German COVID-19 rheumatism register]. / Das deutsche COVID-19-Rheumaregister.

At the beginning of the coronavirus disease 2019 (COVID-19) pandemic in December 2019 there was no available evidence regarding the management of immunosuppressive or immunomodulatory treatment and the potential outcomes of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections in inflammatory rheumatic diseases (IRD). As a result, the Justus Liebig University of Giessen, Germany, in collaboration with the German Society for Rheumatology, established the German COVID-19 register ( www.covid19-rheuma.de ). The COVID-19 register enabled for the first time a systematic documentation and evaluation of viral infections in patients with IRD. The data collection started as early as March 2020. Currently, the register is one of the largest global registers in the field of COVID-19 and IRD. As of 18 December 2023 the register has recorded more than 7100 cases. The first scientific findings on SARS-CoV­2 infections in IRD patients were generated from the register in 2020, showing an association between disease activity of IRD, certain comorbidities, such as cardiovascular diseases and treatment with rituximab, with an unfavorable course. The contents and construction of the database of the register were designed at the conception to allow collaboration and data exchange with other national and international registers (e.g., EULAR COVID-19 register, COVID-19 global rheumatology alliance and the Lean European open survey on SARS-CoV­2 infected patients). In addition, other registers and surveys were initiated. A vaccination register documents the tolerability and possible adverse reactions to COVID-19 vaccination in IRD patients. The data resulted in numerous publications and formed the basis for national and international recommendations for action in the care and vaccination of IRD patients during the COVID-19 pandemic. In summary, the German COVID-19 register has made a significant contribution to the understanding of the course of COVID-19 in IRD patients and has facilitated international collaboration for a better understanding of COVID-19 and IRD.

[Pregnancy and breastfeeding in women with multiple sclerosis]. / Schwangerschaft und Stillzeit bei Frauen mit Multipler Sklerose.

The diagnosis of multiple sclerosis (MS) in women of reproductive age is associated with many uncertainties regarding childbearing and lactation. Pregnancies of MS patients are not usually considered high-risk pregnancies per se. The likelihood of pregnancy complications or adverse pregnancy outcomes is not increased by the disease; however, a careful planning of pregnancy is important in order to choose the treatment option with the greatest benefit for the mother and the least possible risk for the baby. For highly active courses of the disease, anti-CD20 antibodies, cladribine, or continued administration of natalizumab show the best data. Patients with MS can be supported in their desire to breastfeed. If women have had a very active disease course, it is recommended that treatment should be started as soon as possible postpartum. Interferon-beta preparations, glatiramer acetate and ofatumumab are also approved for use during breastfeeding but off-label breastfeeding is also possible with other monoclonal antibodies.

New Perspectives on Development of Curative Strategies for Chronic Hepatitis B.

A functional cure of chronic hepatitis B defined as sustained hepatitis B surface antigen loss after finite course of therapy is rarely achieved with current therapy but is the goal of novel treatments. Understanding the virological and immunological mechanisms of hepatitis B virus persistence has enabled the identification of novel treatment targets, drug discovery, and the evaluation of novel agents in clinical trials. Lessons were learned from early phase 1 and phase 2 trials regarding the antiviral activity and safety profile of these agents. There is a strong rationale to combine agents to reduce viral replication, reduce viral antigen load, invigorate immune responses, and induce specific adaptive immune responses. Nucleos(t)ide analogs will likely remain an essential backbone of future combinations to control viral replication and prevent resistance to antiviral drugs. In this review, we discuss perspectives on approaches to achieving functional cure, with a review of virological and immunological strategies, highlighting challenges and unresolved questions with the various attempts to achieve cure, as well as exploring alternative endpoints such as partial cure and new noninvasive viral and immunological biomarkers to stratify patients and predict/monitor antiviral response.

Effectiveness of the BNT162b2 mRNA COVID-19 vaccine among adolescents with juvenile-onset inflammatory rheumatic diseases.

OBJECTIVES: The effectiveness of the BNT162b2 mRNA COVID-19 vaccine for adolescents with juvenile-onset inflammatory or immune rheumatic diseases (IRDs) is unknown. Several studies have suggested attenuated immunogenicity in patients with IRD. This study evaluated the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in preventing COVID-19 infection in adolescents with juvenile-onset IRD compared with controls without immune rheumatic disease. METHODS: We used data from Clalit Health Services, the largest health-care organization in Israel, to conduct an observational cohort study from February to December 2021, involving 12-18 year-old adolescents diagnosed with IRD. Study outcomes included documented COVID-19 infection in relation to vaccination status and immunomodulatory therapy. We estimated vaccine effectiveness as one minus the risk ratio. Adolescents aged 12-18 years without immune rheumatic disease served as controls. RESULTS: A total of 1639 adolescents with IRD (juvenile idiopathic arthritis, SLE, or familial Mediterranean fever) were included and compared with 524 471 adolescents in the same age range without IRD. There was no difference in COVID-19 infection rates after the second dose of vaccine between those with IRD and controls (2.1% vs 2.1% respectively, P = 0.99). The estimated vaccine effectiveness for adolescents with IRD was 76.3% after the first dose, 94.8% after the second and 99.2% after the third dose. CONCLUSION: We found that the BNT162b2 mRNA vaccine was similarly effective against COVID-19 infection in adolescents with and without IRD. Immunomodulatory therapy did not affect its effectiveness. These results can encourage adolescents with IRD to get vaccinated against COVID-19.

C4d Staining Is Present in Normal Placentas From Pregnancies Prior to Pregnancy Loss Associated With Chronic Histiocytic Intervillositis and Is Reduced by Immunomodulatory Therapy in Subsequent Pregnancies.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is associated with adverse pregnancy outcomes and high recurrence risk. Recent studies suggest that CHI may represent a host-vs-graft rejection, and that C4d immunostain can be used as a marker for complement activation and antibody-mediated rejection in the CHI. MATERIALS AND METHODS: This retrospective cohort study focused on 5 fetal autopsy cases associated with CHI (5 index cases) from 5 women. We analyzed placentas from the index cases (fetal autopsy cases associated with CHI) and placentas from the women's previous and subsequent pregnancies. We assessed the presence and extent of CHI and C4d immunostaining in these placentas. We evaluated each available placenta and graded the severity of CHI as either <50% or ≥50%. Additionally, we conducted C4d immunostaining on one representative section from each placenta and graded the staining levels as follows: 0+ for staining <5%; 1+ for staining between 5% and <25%; 2+ for staining between 25% and <75%; and 3+ for staining ≥75%. RESULTS: Three of the 5 women had pregnancies prior to their index cases (fetal autopsy cases associated with CHI). Despite the absence of CHI in their initial pregnancies, the placentas displayed positive C4d staining with grades of 1+, 3+, and 3+, respectively. These results suggest the presence of complement activation and antibody-mediated rejection in placentas from their prior pregnancies without CHI. Three of the 5 women received immunomodulatory therapy after experiencing pregnancy losses associated with CHI. After treatment, 2 of these women had live births at 35 and 37 gestational weeks, respectively, while the third had a stillbirth at 25 gestational weeks. The severity of CHI and the degree of C4d staining in the placentas decreased in all 3 cases following immunomodulatory therapies. Specifically, the level of C4d staining decreased from 3+ to 2+, 2+ to 0+, and 3+ to 1+ in these 3 cases, respectively. DISCUSSION: In women with a history of recurrent pregnancy loss associated with CHI, C4d immunostaining was present in the placentas from their previous non-CHI pregnancies, suggesting activation of the classical complement pathway and antibody-mediated reaction in their prior non-CHI pregnancies before the development of CHI in subsequent pregnancies. Immunomodulatory therapy may improve pregnancy outcomes by reducing complement activation, as shown by the reduction of C4d immunopositivity in the placentas after immunomodulatory treatment. Although we believe that the study provides valuable insights, we acknowledge that there are limitations to the findings. Therefore, to further elucidate the pathogenesis of CHI, additional research efforts with a collaborative and multidisciplinary approach are necessary.

Immunomodulatory treatment in unclassifiable interstitial lung disease: A retrospective study of treatment response.

BACKGROUND AND OBJECTIVE: The optimal management of unclassifiable Interstitial lung disease (ILD) remains a challenge. The aim of this study was to describe pulmonary function trajectories for patients treated with immunomodulatory therapy and for untreated patients. METHODS: Clinical information and treatment data were obtained retrospectively at two ILD centres. Pulmonary function data were analysed using (1) mixed effects linear regression models with and without clinical covariates and (2) propensity score matching using gender, age, physiology (GAP) stage, smoking and presence of ground glass opacities. RESULTS: Sixty-five percent of the 249 patients included received corticosteroids and/or other immunomodulators. Treated patients had lower forced vital capacity (FVC) (72% vs. 83% predicted) and diffusing capacity for carbon monoxide (DLco) (44% vs. 60% predicted). In mixed effects linear regression, the adjusted change in FVC was -0.22%, [-0.34; -0.11], and -0.15% [-0.28;-0.012] for DLco. The difference in pulmonary function decline between treated and untreated patients was insignificant, -0.082% per month, [-0.28; 0.11], p = 0.10 for FVC and -0.14% per month, [-0.36; 0.079], p = 0.15, for DLco. In propensity score matched analysis, the difference in change in FVC was 0.039% per month, p = 0.12, and for DLco, 0.0085% per month, p = 0.7. CONCLUSION: The pulmonary function trajectories for treated and untreated patients were parallel, despite treated patients having more severe disease at baseline. The persisting differences between the groups suggest no overall effect, although improvement or stabilization may be seen in some patients. Prospective studies are needed to define subsets of patients with unclassifiable interstitial lung disease and their optimal management.

The roles of immune system and autoimmunity in pulmonary arterial hypertension: A review.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by increased pulmonary artery pressure which if left untreated, can lead to poor quality of life and ultimately death. It is a group of conditions and includes idiopathic PAH, familial/hereditary PAH and associated PAH. The condition has been studied for many years and its association with the immune system and in particular autoimmunity has been investigated. The mechanisms for the pathobiology of PAH are unclear although research has highlighted the role of adaptive and innate immune systems in its development. Diagnostics and therapeutic approaches range from cytokine treatments to the use of immunomodulating drugs, although there is still scope for improvements in the field. This article discusses the mechanisms linked to PAH, its association with other conditions and recent therapeutic interventions.

Efficacy of rituximab in anti-myelin-associated glycoprotein demyelinating polyneuropathy: Clinical, hematological and neurophysiological correlations during 2 years of follow-up.

BACKGROUND AND PURPOSE: We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody (anti-MAG) demyelinating polyneuropathy. METHODS: Twenty three anti-MAG-positive polyneuropathic patients were prospectively evaluated before and for 2 years after treatment with RTX 375 mg/m2 . The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (INCAT-ds), modified INCAT sensory score (mISS), Medical Research Council sum score, Patients' Global Impression of Change scale were used, IgM levels were assessed and extensive electrophysiological examinations were performed before (T0) and 1 year (T1) and 2 years (T2) after RTX treatment. RESULTS: At T1 and T2 there was a significant reduction from T0 both in mISS and in INCAT-ds, with a p value < 0.001 in the inferential Friedman's test overall analysis. Ulnar nerve Terminal Latency Index and distal motor latency significantly changed from T0 to T1 and in the overall analysis (p = 0.001 and p = 0.002), and ulnar nerve sensory nerve action potential (SNAP) amplitude was significantly increased at T2 from T1, with a p value < 0.001 in the overall analysis. Analysis of the receiver-operating characteristic curves showed that a 41.8% increase in SNAP amplitude in the ulnar nerve at T2 from T0 was a fair predictor of a mISS reduction of ≥2 points (area under the curve 0.85; p = 0.005; sensitivity: 90.9%, specificity: 83.3%). CONCLUSIONS: This study suggests that RTX is effective in patients with clinically active demyelinating anti-MAG neuropathy over 2 years of follow-up, and that some neurophysiological variables might be useful for monitoring this efficacy.

Chronic inflammatory demyelinating polyneuropathy and psoriasis comorbidity with significantly alleviated in symptoms after secukinumab: case report.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that involves damage to the peripheral nervous system. The course of the disease can progress for more than 8 weeks, with frequent incidences of relapse-remission courses. This article reported a rare combination of CIDP with fluctuating symptoms, recurrence-remission, and comorbidity with psoriasis. CASE PRESENTATION: A 29-year-old male patient with repeated limb weakness and numbness was admitted to the hospital several times in the past six months. He had a history of psoriasis for 6 years, and the medications (clobetasol propionate ointment and calcipotriol ointment) treated for psoriasis were discontinued 1 year ago. During the hospitalization, repeated intravenous injections of human immunoglobulin G (IVIg), immunoadsorption, and secukinumab were performed. Nerve electrophysiology tests, ganglioside autoantibody spectrum tests, and clinical MRC muscle strength scores were performed on a regular basis to confirm the diagnosis of CIDP. The patient was regularly followed up. RESULTS: After repeated rounds of human IVIg and immunoadsorption, the patient's MRC score was increased by ≥ 6 points. The first ganglioside autoantibody spectrum test showed anti-GQ1b IgG ( +) and anti-GM1 IgM ( +) antibodies, and all were negative after re-examination. Finally, the patient was treated with the IL-17A inhibitor secukinumab for psoriasis. During 7 months of follow-up, the CIDP and psoriasis symptoms are relatively stable. CONCLUSION: Combination of IVIg and immunoadsorption was highly effective in treating CIDP complicated with psoriasis. The clinical manifestations of CIDP are diverse. When relapse-remission occurs in the course of the disease, it is necessary to clarify whether it is combined with other autoimmune diseases and should control the autoimmune diseases as soon as possible.

Long-term success treating inflammatory epiretinal neovascularization with immunomodulatory therapy.

PURPOSE: This study aims to report the long-term outcomes of uveitis-associated optic disc and epiretinal neovascularization (NV) treated with immunomodulatory therapy alone. METHODS: This is a retrospective, multi-center chart review conducted at Northwestern University (Chicago, IL) and San Raffaele Scientific Institute (Milan, Italy) from 2014 to 2021 of patients with optic disc and/or retinal neovascularization associated with uveitis. The data collected included age at the time of NV detection, gender, medications, and follow-up period. Imaging was reviewed if available. RESULTS: Eight eyes of six patients were identified. The mean age was 22 years (range 10-52 years); the median follow-up was 3 years (range 6 months to 7 years). All eyes presented with active NV at the time of uveitis onset; 7 eyes were treatment-naïve. None had clinical or angiographic evidence of retinal ischemia. All patients received a variable combination of local steroids, systemic steroids, and systemic immunosuppression. Complete resolution of uveitic NV occurred in all eyes within a median of 8 weeks (ranging 2-20 weeks) from initiating treatment. No NV recurrence was noted. CONCLUSION: Immunomodulatory therapy alone may be successful in achieving long-term control of uveitis-associated NV, without the use of destructive measures.

Idiopathic Multifocal Choroiditis and Punctate Inner Choroidopathy - Evaluation of Risk Factors for Increased Relapse Rate: A 2-Year Prospective Observational Cohort Study.

INTRODUCTION: The aim of this study was to describe the course of disease in patients with idiopathic multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC) and to identify risk factors associated with an increased relapse rate of disease activity. METHODS: In this prospective observational cohort study, demographical and clinical data were collected concerning the relapses rate of disease activity, the conclusions of the multimodal imaging results, treatment, complications, and self-reported quality of life. Disease activity was defined as new inflammatory lesions or active inflammation in preexisting chorioretinal lesions either with or without active choroidal neovascularization (CNV). Linear regression analysis was performed to identify risk factors associated with an increased relapse rate. RESULTS: In total, 122 eyes of 82 patients (93% females) were included with a median age (IQR) of 45 (37-54) years. A history of secondary CNV was present in 66% of the eyes. During follow-up, the best-corrected visual acuity remained stable despite a median relapse rate (IQR) of 1.0 (0.25-3). Cycles of oral corticosteroids were given in 59% of the patients, 72% were treated at baseline or started treatment during follow-up with a disease-modifying antirheumatic drug (DMARD), and 35% with a biological agent in addition to the DMARD. Both a history of secondary CNV (B = 1.2, 95% CI: 0.7-1.7, p = 3.6 × 10-5) and high myopia (<-6 diopters) (B = 0.6, 95% CI: 0.1-1.1, p = 0.02) independently increased the relapse rate of disease activity. DISCUSSION/CONCLUSION: A history of secondary CNV and high myopia were associated with an increased relapse rate of disease activity. Moreover, the results of this study emphasize the challenging character of treating patients with MFC/PIC.

Clinical Characteristics and Outcomes of Coronavirus Disease 2019 Patients Who Received Compassionate-Use Leronlimab.

BACKGROUND: Leronlimab, a monoclonal antibody blocker of C-C chemokine receptor type 5 originally developed to treat human immunodeficiency virus infection, was administered as an open-label compassionate-use therapeutic for coronavirus disease 2019 (COVID-19). METHODS: Twenty-three hospitalized severe/critical COVID-19 patients received 700 mg leronlimab subcutaneously, repeated after 7 days in 17 of 23 patients still hospitalized. Eighteen of 23 received other experimental treatments, including convalescent plasma, hydroxychloroquine, steroids, and/or tocilizumab. Five of 23 received leronlimab after blinded, placebo-controlled trials of remdesivir, sarilumab, selinexor, or tocilizumab. Outcomes and results were extracted from medical records. RESULTS: Mean age was 69.5 ±â€…14.9 years; 20 had significant comorbidities. At baseline, 22 were receiving supplemental oxygen (3 high flow, 7 mechanical ventilation). Blood showed markedly elevated inflammatory markers (ferritin, D-dimer, C-reactive protein) and an elevated neutrophil-to-lymphocyte ratio. By day 30 after initial dosing, 17 were recovered, 2 were still hospitalized, and 4 had died. Of the 7 intubated at baseline, 4 were fully recovered off oxygen, 2 were still hospitalized, and 1 had died. CONCLUSIONS: Leronlimab appeared safe and well tolerated. The high recovery rate suggested benefit, and those with lower inflammatory markers had better outcomes. Some, but not all, patients appeared to have dramatic clinical responses, indicating that unknown factors may determine responsiveness to leronlimab. Routine inflammatory and cell prognostic markers did not markedly change immediately after treatment, although interleukin-6 tended to fall. In some persons, C-reactive protein clearly dropped only after the second leronlimab dose, suggesting that a higher loading dose might be more effective. Future controlled trials will be informative.

COVID-19 prevalence and outcomes in patients receiving biologic therapies at an infusion center in New York City.

To better understand COVID-19 infection in patients receiving biologic and immunomodulatory therapies, we evaluated prevalence and outcomes for symptomatic cases of COVID-19 at a large therapeutic infusion center in New York City during the height of the pandemic. 2074 patients received treatment with biologic infusions at our center between March and May 2020, and 34 patients developed symptomatic COVID-19 infection, for an overall low rate of 1.64%. The majority of infections and deaths were in a small subset of patients with a primary immunodeficiency. Patients with inflammatory or autoimmune conditions requiring biologic therapies tended to have mild cases. Higher inflammatory responses were observed in patients who died.

Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). METHODS: In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint. RESULTS: At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30-1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302.

Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis.

The treatment of multiple sclerosis (MS), the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS), continues to transform. In recent years, a number of novel and increasingly effective disease-modulatory therapies (DMTs) have been approved, including oral fumarates and selective sphingosine 1-phosphate modulators, as well as cell-depleting therapies such as cladribine, anti-CD20 and anti-CD52 monoclonals. Amongst DMTs in clinical development, inhibitors of Bruton's tyrosine kinase represent an entirely new emerging drug class in MS, with three different drugs entering phase III trials. However, important remaining fields of improvement comprise tracking of long-term benefit-risk with existing DMTs and exploration of novel treatment targets relating to brain inherent disease processes underlying the progressive neurodegenerative aspect of MS, which accumulating evidence suggests start already early in the disease process. The aim here is to review current therapeutic options in relation to an improved understanding of the immunopathogenesis of MS, also highlighting examples where controlled trials have not generated the desired results. An additional aim is to review emerging therapies undergoing clinical development, including agents that interfere with disease processes believed to be important for neurodegeneration or aiming to enhance reparative responses. Notably, early trials now have shown initial evidence of enhanced remyelination both with small molecule compounds and biologicals. Finally, accumulating evidence from clinical trials and post-marketing real-world patient populations, which underscore the importance of early high effective therapy whilst maintaining acceptable tolerability, is discussed.

An evidence-based guide to SARS-CoV-2 vaccination of patients on immunotherapies in dermatology.

Immune-mediated diseases and immunotherapeutics can negatively affect normal immune functioning and, consequently, vaccine safety and response. The COVID-19 pandemic has incited research aimed at developing a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. As SARS-CoV-2 vaccines are developed and made available, the assessment of anticipated safety and efficacy in patients with immune-mediated dermatologic diseases and requiring immunosuppressive and/or immunomodulatory therapy is particularly important. A review of the literature was conducted by a multidisciplinary committee to provide guidance on the safety and efficacy of SARS-CoV-2 vaccination for dermatologists and other clinicians when prescribing immunotherapeutics. The vaccine platforms being used to develop SARS-CoV-2 vaccines are expected to be safe and potentially effective for dermatology patients on immunotherapeutics. Current guidelines for the vaccination of an immunocompromised host remain appropriate when considering future administration of SARS-CoV-2 vaccines.

The Challenging Management of Cancer: An Immunonephrologist's Perspective.

INTRODUCTION: Onconephrology is an emerging medical subspecialization that focuses on the numberless interrelations between cancer and kidney diseases. Tumor cells evade immune surveillance through activation of immune checkpoint pathways that suppress antitumor immune responses. By blocking checkpoints, new anticancer agents disrupt immune homeostasis but potentially induce immune-mediated diseases. Nephrologists and nephroimmunologists should be able to treat the nephrotoxic sequelae of cancer therapy and ensure continuation of the life-saving treatment. METHODS: Thirty-seven renal biopsies have been carried out over 42 months in oncologic patients, that is, 5.2% of the total native renal biopsies were carried out in the same period. The commonest diagnoses (>6 cases) were interstitial tubular nephritis, membranous glomerulopathy, IgA nephropathy, vasculitis, and focal and segmental glomerulosclerosis. CASE PRESENTATION: Three example cases, including focusing on key questions which could involve the nephrologists are reported in detail. They include a cancer-related Goodpasture Syndrome, the peculiar toxic effects of pemetrexed on tubular cells, and the intriguing relationship between bevacizumab and cryoglobulinemic glomerulonephritis. CONCLUSION: As shown by these 3 example cases, nephrologists need to be open-minded with regard to kidney biopsy in order to get a timely diagnosis. Nephrologists also need to improve their knowledge of cancer biology and therapy in order to prevent kidney problems, manage therapy-related immune-mediated disorders, and improve patient life expectancy.