Gut-associated lymphoid tissue attrition associates with response to anti-α4ß7 therapy in ulcerative colitis.

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4ß7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (ß7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4ß7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of ß7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC.

[Treatment of autoimmune hepatitis-First-line, second-line and third-line treatment]. / Therapie der Autoimmunhepatitis ­ Erst­, Zweit- und Drittlinientherapie.

Autoimmune hepatitis (AIH) is a rare autoimmune inflammation of the liver mostly with a chronic course, which can also be acutely manifested up to acute liver failure. It affects women 3-4 times more frequently than men and can be diagnosed in all age groups. In one third of the patients a liver cirrhosis is present at the time of diagnosis. It is characterized by a hepatic inflammation pattern, a polyclonal hypergammaglobulinemia of immunoglobulin G and the detection of autoantibodies. A liver biopsy is necessary to make the diagnosis. The AIH is histologically characterized in particular by a lymphoplasmacytic infiltrate in the portal fields. In cases with a relevant disease activity, AIH is typically treated by immunosuppression. The immunosuppressive treatment is associated with a prevention of disease progression to liver cirrhosis and a better survival. The success of treatment is measured by achieving biochemical remission, i.e., normalization of the transaminase and immunoglobulin G levels as a good noninvasive predictor of a histological remission. Another treatment target is an improvement of the symptoms of the patient. The first-line treatment consists of a glucocorticoid, mostly prednisolone or in cases without advanced fibrosis budesonide, and azothioprine. For reduction of steroid-specific treatment side effects the maintenance treatment should be carried out steroid-free whenever possible. In cases of insufficient response to azothioprine or side effects a treatment attempt using antimetabolites, such as 6­mercaptopurine or mycophenolate mofetil is primarily carried out as second-line treatment. For patients who do not achieve biochemical remission through first-line or second-line treatment, a variety of medications are available for third-line treatment, e.g., rituximab, calcineurin inhibitors or antitumor necrosis factor (anti-TNF) antibodies. Third-line treatment should be carried out in expert centers and registered in the European Reference Network for Rare Liver Diseases in order to improve the currently sparse database for these forms of treatment in the future.

Clinical profile and challenges faced in the management of optic neuritis: the Indian scenario.

PURPOSE: Optic neuritis (ON) is a relatively common ophthalmic disease that has recently received renewed attention owing to immunological breakthroughs. We studied the profile of patients with ON with special reference to antibody-mediated ON and the challenges faced in its management. METHODS: Case records of patients with ON presenting to a tertiary eye-care center in South India were analyzed. Data on demographics, presenting visual acuity (VA), clinical features, seropositivity for aquaporin-4 immunoglobulin G (AQP4-IgG) and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG), details of magnetic resonance imaging (MRI) of orbits and brain, and treatment were collected. RESULTS: Among 138 cases with acute ON, male: female ratio was 1:2. Isolated ON was present in 41.3% of cases. Antibody testing of sera was performed in 68 patients only due to financial limitations. Among these, 48.5% were MOG-IgG-seropositive, 11.76% were AQP4-IgG-seropositive, and 30.88% samples were double seronegative. Other causes included multiple sclerosis (n = 4), lactational ON (n = 4), tuberculosis (n = 2), invasive perineuritis (n = 2), COVID-19 vaccination (n = 2), and COVID-19 (n = 1). The mean presenting best corrected visual acuity (BCVA) was 1.31 ± 1.16 logMAR (logarithm of the minimum angle of resolution). The mean BCVA at 3 months was 0.167 ± 0.46 logMAR. Only initial VA ≤ 'Counting fingers' (CF) had a significant association with the visual outcome for final VA worse than CF. The steep cost of investigations and treatment posed challenges for many patients in the management of ON. CONCLUSION: MOG-IgG-associated ON is common in India. Unfortunately, financial constraints delay the diagnosis and timely management of ON, adversely affecting the outcome.

Human Fc gamma receptor IIIA blockade inhibits platelet destruction in a humanized murine model of ITP.

ABSTRACT: Fc gamma receptor (FcγR) IIIA is an important receptor for immunoglobulin G (IgG) and is involved in immune defense mechanisms as well as tissue destruction in some autoimmune diseases including immune thrombocytopenia (ITP). FcγRIIIA on macrophages can trigger phagocytosis of IgG-sensitized platelets, and prior pilot studies observed blockade of FcγRIIIA increased platelet counts in patients with ITP. Unfortunately, although blockade of FcγRIIIA in patients with ITP increased platelet counts, its engagement by the blocking antibody drove serious adverse inflammatory reactions. These adverse events were postulated to originate from the antibody's Fc and/or bivalent nature. The blockade of human FcγRIIIA in vivo with a monovalent construct lacking an active Fc region has not yet been achieved. To effectively block FcγRIIIA in vivo, we developed a high affinity monovalent single-chain variable fragment (scFv) that can bind and block human FcγRIIIA. This scFv (17C02) was expressed in 3 formats: a monovalent fusion protein with albumin, a 1-armed human IgG1 antibody, and a standard bivalent mouse (IgG2a) antibody. Both monovalent formats were effective in preventing phagocytosis of ITP serum-sensitized human platelets. In vivo studies using FcγR-humanized mice demonstrated that both monovalent therapeutics were also able to increase platelet counts. The monovalent albumin fusion protein did not have adverse event activity as assessed by changes in body temperature, whereas the 1-armed antibody induced some changes in body temperature even though the Fc region function was impaired by the Leu234Ala and Leu235Ala mutations. These data demonstrate that monovalent blockade of human FcγRIIIA in vivo can potentially be a therapeutic strategy for patients with ITP.

Pharmacodynamics and Mechanism of Astragali Radix and Anemarrhenae Rhizoma in Treating Chronic Heart Failure by Inhibiting Complement Activation.

Astragali radix (AR) and anemarrhenae rhizoma (AAR) are used clinically in Chinese medicine for the treatment of chronic heart failure (CHF), but the exact therapeutic mechanism is unclear. In this study, a total of 60 male C57BL/6 mice were divided into 5 groups, namely sham, model, AR, AAR, and AR-AAR. In the sham group, the chest was opened without ligation. In the other groups, the chest was opened and the transverse aorta was ligated to construct the transverse aortic constriction model. After 8 weeks of feeding, mice were given medicines by gavage for 4 weeks. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were detected by echocardiography. Heart weight index (HWI) and wheat germ agglutinin staining were used to evaluate cardiac hypertrophy. Hematoxylin-eosin staining was used to observe the pathological morphology of myocardial tissue. Masson staining was used to evaluate myocardial fibrosis. The content of serum brain natriuretic peptide (BNP) was detected by enzyme-linked immunosorbent assay kit. The content of serum immunoglobulin G (IgG) was detected by immunoturbidimetry. The mechanism of AR-AAR in the treatment of CHF was explored by proteomics. Western blot was used to detect the protein expressions of complement component 1s (C1s), complement component 9 (C9), and terminal complement complex 5b-9 (C5b-9). The results show that AR-AAR inhibits the expression of complement proteins C1s, C9, and C5b-9 by inhibiting the production of IgG antibodies from B cell activation, which further inhibits the complement activation, attenuates myocardial fibrosis, reduces HWI and cardiomyocyte cross-sectional area, improves cardiomyocyte injury, reduces serum BNP release, elevates LVEF and LVFS, improves cardiac function, and exerts myocardial protection.

Ravulizumabe no tratamento da hemoglobinúria paroxística noturna / Ravulizumabe not treated for paroxysmal nocturnal hemoglobinuria

INTRODUÇÃO: A Hemoglobinúria Paroxística Noturna (HPN) é uma doença rara, com incidência anual estimada de 1,3 novos casos por um milhão de indivíduos. Esta se caracteriza pela ativação descontrolada do complemento, que pode levar à hemólise intravascular (que por sua vez causa os episódios de hemoglobinúria), danos a órgãos (por exemplo, insuficiência renal e hipertensão pulmonar), eventos trombóticos, aumento da morbidade e mortalidade. Inibidores do C5 são opções de tratamento primário para esta doença, tendo sido o primeiro desta classe licenciado no mundo o eculizumabe em 2007. Em 2019 foi lançado o PCDT da HPN, que conta com a inclusão do eculizumabe. Dados de uma coorte nacional de pacientes com HPN mostram que 16% dos pacientes tiveram síndrome mielodisplásica e cerca de metade da amostra apresentava outras anemias aplásticas e/ou outras síndromes de falha de produção de outras linhas celulares sanguíneas (plaquetas e leucócitos). Embolia venosa e trombose venosa ocorreram em 4

CC-96673 (BMS-986358), an affinity-tuned anti-CD47 and CD20 bispecific antibody with fully functional fc, selectively targets and depletes non-Hodgkin's lymphoma.

Cluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a "don't eat me" signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia. To overcome those challenges a bispecific approach was taken. CC-96673, a humanized IgG1 bispecific antibody co-targeting CD47 and CD20, is designed to bind CD20 with high affinity and CD47 with optimally lowered affinity. As a result of the detuned CD47 affinity, CC-96673 selectively binds to CD20-expressing cells, blocking the interaction of CD47 with SIRPα. This increased selectivity of CC-96673 over monospecific anti-CD47 approaches allows for the use of wild-type IgG1 Fc, which engages activating crystallizable fragment gamma receptors (FcγRs) to fully potentiate macrophages to engulf and destroy CD20+ cells, while sparing CD47+CD20- normal cells. The combined targeting of anti-CD20 and anti-CD47 results in enhanced anti- tumor activity compared to anti-CD20 targeting antibodies alone. Furthermore, preclinical studies have demonstrated that CC-96673 exhibits acceptable pharmacokinetic properties with a favorable toxicity profile in non-human primates. Collectively, these findings define CC-96673 as a promising CD47 × CD20 bispecific antibody that selectively destroys CD20+ cancer cells via enhanced phagocytosis and other effector functions.

Evaluation of RNase therapy in systemic lupus erythematosus: a randomised phase 2a clinical trial of RSLV-132.

BACKGROUND: Circulating, extracellular RNA is the primary trigger of type I interferon in systemic lupus erythematosus (SLE), and interferon is known to play a central pathogenic role in the disease. RSLV-132 is a catalytically active human RNase molecule fused to human IgG1 Fc designed to digest RNA and thereby decrease the chronic inflammation associated with SLE. The drug was evaluated in a cohort of patients with SLE with moderate-severe cutaneous disease activity and the presence of RNA immune complexes. The primary objective of the study was the assessment of the impact of 13 doses of 10 mg/kg RSLV-132 over 6 months on the mean Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score. METHODS: Sixty-five patients meeting the entry criteria of a baseline CLASI score of 10 or greater and positivity of at least one of five autoantibodies to RNA-binding proteins (SM/RNP, SSA/Ro, SSB/La, Sm, RNP) were randomly assigned (2:1) to receive 13 doses of RSLV-132 10 mg/kg or placebo, respectively. Participants received study drug for 24 weeks on days 1, 8, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141 and 155 with an end-of-treatment visit on day 169 and a follow-up visit at the end of the study on day 215. The primary objective was assessed on days 85 and 169. Secondary objectives included assessment of systemic disease activity using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the British Isles Lupus Assessment Group 2004 Index and the Physician's Global Assessment. Data from these instruments were used to calculate the SLE Responder Index 4 (SRI-4) and the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) scores. RESULTS: The mean CLASI score change from baseline at day 169 was -5.7 (±7.0) in the placebo group and -6.2 (±8.5) in the RSLV-132 group. A subgroup of participants with moderate-severe systemic disease activity and high baseline SLEDAI scores (≥9) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high SLEDAI subgroup had a greater percentage of BICLA responses (62% vs 44%) and SRI-4 responses (23% vs 11%) as compared with placebo. A second subgroup of participants with high baseline CLASI scores (≥21) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high CLASI subgroup had a greater percentage of BICLA responses (28% vs 8%) and SRI-4 responses (39% vs 8%) as compared with placebo. CONCLUSIONS: Six months of RSLV-132 therapy consisting of a weekly loading dose of RSLV-132 for 1 month, followed by 5 months of biweekly administrations did not significantly improve the mean CLASI score relative to placebo in this cohort of patients with SLE. The study entry criteria selected patients with moderate-severe cutaneous disease activity and no minimum SLEDAI score, which resulted in a wide range of systemic disease activity from inactive to severe as measured by SLEDAI. When the participants with higher SLEDAI and CLASI scores were analysed, a trend towards clinical improvement favouring RSLV-132 was observed. The results warrant further evaluation of RSLV-132 in SLE and suggest that patients with more active systemic disease are most likely to benefit from RNase therapy.

The role of oligoclonal band count and IgG index in treatment response and disease activity in multiple sclerosis.

BACKGROUND/AIM: Multiple sclerosis (MS) is an inflammatory demyelinating central nervous system (CNS) disease. Among the paraclinical tests, brain and spinal Magnetic Resonance Imaging (MRI) is primarily involved in the diagnosis process, and cerebrospinal fluid (CSF) analysis is fundamental in diagnosing MS and the differential diagnosis. A positive relationship was demonstrated between oligoclonal band (OCB) positivity, CSF band number and immunoglobulin G(IgG) index. The study aimed to evaluate whether the number of OCB can predict disease activity and determine a correlation with the IgG index. METHODS: Our study included 401 MS patients who had relapsing-remitting multiple sclerosis (RRMS), primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), clinic isolated syndrome (CIS), radiologic isolated syndrome (RIS), Neuromyelitis optica spectrum disorder (NMOSD) and Acute disseminated encephalomyelitis (ADEM) with OCB number groups of 2-4, 4-8, 8-12, and 12 and above. RESULTS: No significant correlation was observed between IgG index, pre-and post-treatment EDSS (Expanded Disability Status Scale Scores) and disease-modifying therapies (DMT). Drug response was better in the patient group with band number between 2 and 8 and post-treatment EDSS scores were lower (1.62±0.44). CONCLUSION: The study results suggested that band number may be as valuable as the IgG index and a predictive biomarker for disease activity.

Immune checkpoint inhibitor use and the incidence of hepatitis B virus reactivation or immune-related hepatitis in non-small cell lung cancer patients with chronic hepatitis B.

BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.

Advancements in Allergen Immunotherapy for the Treatment of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that affects individuals of all age groups, manifesting as a spectrum of symptoms varying from mild to severe. Allergen immunotherapy (AIT) involves the administration of allergen extracts and has emerged as a potential treatment strategy for modifying immune responses. Its pathogenesis involves epidermal barrier dysfunction, microbiome imbalance, immune dysregulation, and environmental factors. Existing treatment strategies encompass topical steroids to systemic agents, while AIT is under investigation as a potential immune-modifying alternative. Several studies have shown reductions in the severity scoring of atopic dermatitis (SCORAD) scores, daily rescue medication use, and visual analog scale (VAS) scores following AIT. Biomarker changes include increased IgG4 levels and decreased eosinophil counts. This review provides valuable insights for future research and clinical practice, exploring AIT as a viable option for the management of AD.

Population pharmacokinetics of immunoglobulin G after intravenous, subcutaneous, or hyaluronidase-facilitated subcutaneous administration in immunoglobulin-naive patients with primary immunodeficiencies.

Immunoglobulin G (IgG) replacement therapy is the standard of care for patients with primary immunodeficiencies with antibody deficiencies. Intravenous (IVIG), subcutaneous (SCIG), and hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) therapies differ in their pharmacokinetic (PK) profiles, administration routes, and dosing regimens. Information on use of subcutaneous therapy in IgG treatment-naive patients is limited. This study used population pharmacokinetic (popPK) model-based simulations to characterize IgG PKs in IgG-naive patients with varying disease severity across several IVIG, SCIG, and fSCIG dosing regimens. An integrated popPK model, developed and validated using data from eight clinical trials, was utilized to simulate scenarios that varied by therapy, loading regimen, maintenance dose (equivalent to 400, 600, or 800 mg/kg every 4 weeks [Q4W]), and baseline endogenous total IgG concentration (1.5 or 4.0 g/L). Simulations were performed for age groups of 2-<6, 6-<12, 12-<18, and ≥18 years. Steady-state serum trough IgG concentrations (Cmin,ss), proportion of patients achieving Cmin,ss ≥ 7 g/L, and days taken to reach this threshold were summarized. SCIG provided greater mean Cmin,ss values than IVIG and fSCIG for any scenario. Across all therapies, Cmin,ss tended to increase with age, dose, and endogenous concentration. Although the findings are model-based and not a summarization of real-world observations, doses ≥ 800 mg/kg Q4W with corresponding loading regimens are likely to be clinically appropriate for achieving target IgG concentrations in treatment-naive patients in a timely manner, especially at low endogenous starting concentrations. Therapy-specific dose adjustment based on baseline endogenous IgG concentration, clinical status, and patient characteristics may be warranted.

A nomogram based on ultrasound scoring system for differentiating between immunoglobulin G4-related sialadenitis and primary Sjögren syndrome.

OBJECTIVES: Accurate distinguishing between immunoglobulin G4-related sialadenitis (IgG4-RS) and primary Sjögren syndrome (pSS) is crucial due to their different treatment approaches. This study aimed to construct and validate a nomogram based on the ultrasound (US) scoring system for the differentiation of IgG4-RS and pSS. METHODS: A total of 193 patients with a clinical diagnosis of IgG4-RS or pSS treated at our institution were enrolled in the training cohort (n = 135; IgG4-RS = 28, pSS = 107) and the validation cohort (n = 58; IgG4-RS = 15, pSS = 43). The least absolute shrinkage and selection operator regression algorithm was utilized to screen the most optimal clinical features and US scoring parameters. A model for the differential diagnosis of IgG4-RS or pSS was built using logistic regression and visualized as a nomogram. The performance levels of the nomogram model were evaluated and validated in both the training and validation cohorts. RESULTS: The nomogram incorporating clinical features and US scoring parameters showed better predictive value in differentiating IgG4-RS from pSS, with the area under the curves of 0.947 and 0.958 for the training cohort and the validation cohort, respectively. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSIONS: A nomogram based on the US scoring system showed favourable predictive efficacy in differentiating IgG4-RS from pSS. It has the potential to aid in clinical decision-making.

Detrimental impact of immunosuppressive burden on clinical course in patients with Cytomegalovirus infection after liver transplantation.

INTRODUCTION: Cytomegalovirus (CMV)-infection and reactivation remain a relevant complication after liver transplantation (LT). The recipient and donor serum CMV-IgG-status has been established for risk stratification when choosing various pharmaceutical regimens for CMV-prophylaxis in the last two decades. However, factors influencing course of CMV-infection in LT remain largely unknown. In this study, the impact of immunosuppressive regimen was examined in a large cohort of patients. METHODS: All patients that underwent primary LT between 2006 and 2018 at the Charité-Universitaetsmedizin, Berlin, were included. Clinical course as well as histological and laboratory findings of patients were analyzed our prospectively maintained database. Univariate and multivariate regression analysis for impact of variables on CMV-occurrence was conducted, and survival was examined using Kaplan-Meier analysis. RESULTS: Overall, 867 patients were included in the final analysis. CMV-infection was diagnosed in 325 (37.5%) patients after transplantation. Significantly improved overall survival was observed in these patients (Log rank = 0.03). As shown by correlation and regression tree classification and regression tree analysis, the recipient/donor CMV-IgG-status with either positivity had the largest influence on CMV-occurrence. Analysis of immunosuppressive burden did not reveal statistical impact on CMV-infection, but statistically significant inverse correlation of cumulative tacrolimus trough levels and survival was found (Log rank < .001). Multivariate analysis confirmed these findings (p = .02). DISCUSSION: CMV-infection remains of clinical importance after LT. Undergone CMV-infection of either recipient or donor requires prophylactic treatment. Additionally, we found a highly significant, dosage-dependent impact of immunosuppression (IS) on long-term outcomes for these patients, underlying the importance of minimization of IS in liver transplant recipients.

Antibodies against oxidized LDL and atherosclerosis in rheumatoid arthritis patients treated with biological agents: a prospective controlled study.

OBJECTIVES: The aim of this study was to investigate the relation among atherosclerosis, antibodies against oxidized LDL (anti-oxLDL), and inflammation in rheumatoid arthritis (RA) patients treated with biological (b) disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Fifty-nine patients who were receiving conventional synthetic DMARDs and were eligible for treatment with a biological agent were included in the study. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and IgG antibodies against oxidized LDL (anti-oxLDL) as well as carotid intima-media thickness (cIMT) were determined before and after 6 months of treatment. Thirty-one healthy individuals were used as a control group. RESULTS: At baseline, RA patients had lower TC and HDL-C levels and increased cIMT compared to controls. After a 6-month follow-up, the re-evaluation of carotids revealed a statistically important decrease of cIMT values. This observation was accompanied by a statistically important elevation of HDL-C levels and a reduction of the titer of anti-oxLDL antibodies regardless of the bDMARD that was administered. No statistically significant association was found between the cIMT and anti-oxLDL, HDL-C, CRP, or DAS28 score neither before nor 6 months after treatment using linear regression analyses adjusted for age and gender. CONCLUSIONS: We provide evidence that atherogenic lipid profile and ongoing atherosclerosis which characterize RA patients appear to improve after biological therapy, and we also suggest a possible atherogenic effect of IgG anti-ox LDL antibodies.

Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study.

BACKGROUND: Patients with relapsed/refractory multiple myeloma are at increased risk of infection. Infections during treatment with teclistamab, the first B-cell maturation antigen-directed bispecific antibody approved for triple-class-exposed relapsed/refractory multiple myeloma, was examined in the phase 1/2 MajesTEC-1 study. METHODS: Patients (N = 165) received subcutaneous teclistamab 1.5 mg/kg weekly after a step-up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2-4 days). Patients were monitored frequently for infections; prophylaxis and management were per institutional guidelines. RESULTS: At a median follow-up of 22.8 months (range, 0.3-33.6), infections were reported in 132 patients (80.0%). Grade 3/4 infections occurred in 91 patients (55.2%), including COVID-19 (21.2%), respiratory infections (19.4%), Pneumocystis jirovecii pneumonia (4.2%), viral infections (4.2%), and gastrointestinal infections (1.2%). Twenty-one patients died from infections (18 from COVID-19). Median time to first onset of any-grade and grade 3 to 5 infections was 1.7 and 4.2 months, respectively. Overall, 70.9% of patients had ≥1 postbaseline immunoglobulin G (IgG) level <400 mg/dL; median time to IgG <400 mg/dL was 1.2 months (range, 0.2-19.8) and 46.1% received ≥1 dose of IgG replacement. Grade 3/4 neutropenia occurred in 65.5% of patients (median time to grade ≥3 neutropenia/febrile neutropenia was 2.3 months [range, 0-18.1]). CONCLUSION: Based on the infection profile of B-cell maturation antigen-targeted bispecific antibodies such as teclistamab, it is recommended that clinicians and patients remain vigilant for a range of infection types throughout treatment to facilitate prompt intervention. Appropriate screening, prophylaxis, and management of infections, hypogammaglobulinemia, and neutropenia are important. CLINICAL TRIAL REGISTRATION: NCT03145181/NCT04557098 (ClinicalTrials.gov) PLAIN LANGUAGE SUMMARY: Before starting teclistamab, patients should be up to date with vaccinations (including COVID-19) and screened for hepatitis B and C and HIV. Teclistamab should not be given to patients with any active infections. Prophylactic antimicrobials should be administered per institutional guidelines. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex/varicella zoster virus is recommended during teclistamab treatment. Close monitoring of infections and immunoglobulin G (IgG) levels should continue throughout teclistamab treatment. IgG replacement (administered every 3-6 weeks) should be used to maintain IgG ≥400 mg/dL. Growth factors should be considered for grade ≥3 neutropenia with infection/fever and grade 4 neutropenia.

Biomarkers of Autoimmune Chronic Spontaneous Urticaria.

PURPOSEOF REVIEW: Chronic spontaneous urticaria and chronic inducible urticaria (CSU/CindU) are caused by mast cell and basophil activation leading to degranulation and the release of histamine and several other mediators. Three kinds of factors can trigger mast cells in CSU: (1) activation of stimulating receptor(s) on the mast cell membrane, (2) upregulation of certain receptor(s), and (3) intracellular dysregulation in signaling with overexpression of the spleen tyrosine kinase (SYK) or reduced activation of the inhibitory Src homology 2 (SH2)-containing inositol phosphatases (SHIP)-related pathways. In CSU, two major endotypes exist based on the primary receptor activating mechanism: type I hypersensitivity (IgE-mediated, directed against auto-allergens) and type IIb (autoimmune, via IgG autoantibodies directed against IgE or the IgE-receptor). Their treatment responses vary. We discuss in vitro and in vivo biomarkers. RECENT FINDINGS: Patients with auto-allergic CSU have clinical characteristics that can distinguish them partly from those with autoimmune CSU. Most importantly, their disease generally presents a less aggressive course, a better response to second generation (up-dosed) antihistamines and a good response to omalizumab, if necessary. Meanwhile, autoimmune CSU/CindU patients fare less well and often need immunosuppressive drugs. Biomarkers that might help endotype CSU/CindU patients and select the most appropriate treatment, dose, and duration, e.g., for autoallergic CSU, high total IgE and IgE against auto-allergens; for autoimmune CSU, low IgE, basopenia, and IgG against autoantigens like thyroid peroxidase and a positive autologous serum skin test (but sometimes also positive in autoallergy). Some biomarkers are easily accessible but of low specificity; others are highly specific but more futuristic.

Distinct patterns of auto-reactive antibodies associated with organ-specific immune-related adverse events.

The roles of preexisting auto-reactive antibodies in immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy are not well defined. Here, we analyzed plasma samples longitudinally collected at predefined time points and at the time of irAEs from 58 patients with immunotherapy naïve metastatic non-small cell lung cancer treated on clinical protocol with ipilimumab and nivolumab. We used a proteomic microarray system capable of assaying antibody reactivity for IgG and IgM fractions against 120 antigens for systemically evaluating the correlations between auto-reactive antibodies and certain organ-specific irAEs. We found that distinct patterns of auto-reactive antibodies at baseline were associated with the subsequent development of organ-specific irAEs. Notably, ACHRG IgM was associated with pneumonitis, anti-cytokeratin 19 IgM with dermatitis, and anti-thyroglobulin IgG with hepatitis. These antibodies merit further investigation as potential biomarkers for identifying high-risk populations for irAEs and/or monitoring irAEs during immunotherapy treatment. Trial registration: ClinicalTrials.gov identifier: NCT03391869.

Ustequinumabe para o tratamento de pacientes com doença de Crohn ativa moderada a grave / Ustequinumab for the treatment of patients with moderate to severe Crohn's disease

INTRODUÇÃO: A DC é uma doença inflamatória intestinal resultante da ativação imune inadequada da mucosa, caracterizada por períodos de manifestações agudas e remissões, o que torna o tratamento desta condição complexo. De forma geral, o tratamento inclui a fase de indução e em seguida uma fase de manutenção. Nos casos considerados moderados a graves, em ambas as fases, corticosteroides, azatioprina e metotrexato podem ser utilizados, a depender da resposta de cada paciente. No entanto, nos casos em que há contraindicação, falha ou intolerância ao tratamento, os anti-TNF e o UST (antiinterleucina 12/23) são os biológicos de escolha. PERGUNTA: O UST é uma alternativa segura e eficaz para pacientes com DC ativa moderada a grave (1) com indicação de terapia biológica e com contraindicação aos anti-TNF e (2) com indicação de terapia biológica e com falha ou intolerância aos anti-TNF? O demandante externo elaborou a seguinte pergunta de pesquisa: Stelara®(UST) é eficaz e seguro no tratamento de pacientes com doença de Crohn ativa moderada-grave, após falha ou contraindicados ao tratamento com terapias anti-TNF, em comparação com placebo + tratamento convencional? EVIDÊNCIAS CLÍNICAS: Foram incluídos 13 estudos, sendo seis Revisões Sistmáticas com meta-análise e sete Ensaios Clínicos Randomizados (ECRs). Dentre os efeitos desejáveis, o UST demonstrou sup

Pembrolizumabe em primeira linha de tratamento em indivíduos com câncer de cólon ou reto metastático / Pembrolizumab in the first line of treatment in individuals with colon cancer or metastatic challenge

INTRODUÇÃO: O pembrolizumabe é um anticorpo monoclonal com indicação em bula para vários tipos de câncer, inclusive para o tratamento de primeira linha em adultos com câncer de cólon e reto metastático com instabilidade microssatélite (MSI) e deficiência de enzimas de reparo (dMMR) do DNA. Atualmente, pembrolizumabe está incorporado no SUS para o tratamento de melanoma avançado não cirúrgico e metastático. PERGUNTA DE PESQUISA: O medicamento pembrolizumabe é eficaz, seguro, custo-efetivo e viável economicamente como primeira linha de tratamento em adultos com câncer de cólon ou reto metastático com MSI ou dMMR comparado a qualquer opção usual na prática clínica? SÍNTESE DAS EVIDÊNCIAS CIENTÍFICAS: Foi identificado um ECR (KEYNOTE-177) no qual se avaliou o pembrolizumabe para tratamento de adultos com câncer de cólon ou reto metastático com alta instabilidade de microssatélites e deficiência em enzimas de reparo em primeira linha de tratamento. Comparou-se pembrolizumabe com cuidado padrão (mFOLFOX6 ou FOL