Autoimmune Events Research Articles

A phase I study of duvelisib in combination with oral azacitidine (CC-486) in relapsed lymphoid malignancies.

TPS7594 Background: Phosphoinositide 3-kinase (PI3K) inhibitors have shown promising activity in lymphoid malignancies such as mature T cell lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. Duvelisib’s PI3K-δ and PI3K-γ activity in T cell lymphoma is promising as a single agent (Horwitz, Koch et al. 2018). While the safety profile can generally be managed, certain autoimmune adverse events may limit its adaptation in clinical practice. Azacitidine, a pyrimidine nucleoside analog of cytidine, is active in T cell lymphoma (Saillard, Guermouche et al. 2017) as well as in DLBCL (Martin, Bartlett et al. 2018). Hypomethylators could enhance the activity of PI3K inhibitors through increasing PTEN expression (Spangle, Roberts et al. 2017), and upregulation of tumor suppressor genes (Zuo, Liu et al. 2011). Duvelisib’s immune mediated adverse events may be related to shifts in T cell differentiation towards Th17 phenotype and decreases in T reg differentiation that found to be more pronounced in patients with higher immune related toxicity (Gadi, Kasar et al. 2019). Studies have shown that T regs can be induced from Cd4+CD25- T cells using DNA methyltransferase inhibition with azacitidine (Fagone, Mazzon et al. 2018). Thus, the intermittent administration of azacytidine can potentially restore the balance by increasing T regs to decrease the autoimmune toxicity while maintaining Th17 phenotype that enhances tumor killing as shown in myelodysplastic syndrome (Jia, Yang et al. 2020). Methods: This is a 3+3 phase I dose escalation study designed to determine the maximum tolerated dose (MTD) of CC-486 in combination with duvelisib in patients with lymphoid malignancies. The MTD is defined as the highest dose with an observed incidence of dose limiting toxicity (DLT) in no more than one out of six patients treated at a particular dose level. Secondary endpoints include best overall response, disease control rate and duration of response. Exploratory end points will be biomarker driven with focus on the composition of different T cell compartments during the administration of the combination. Efficacy biomarkers will include measuring the phosphorylation of AKT in peripheral CD3+ T cells. Oral duvelisib will be given continuously with the dose escalation maintained during the first 2 cycles while CC-486 schedule will be 14 days on/14 days off. The first cohort of patients are enrolled, and are in the DLT testing period. Clinical trial information: NCT05065866.

Real-world evidence for cladribine tablets in multiple sclerosis: further insights into efficacy and safety.

Cladribine (CLAD) is a purine nucleoside analog approved in tablet form to treat highly active multiple sclerosis (MS). CLAD tablets are the first oral therapy with an infrequent dosing schedule, administered in two annual treatment courses, each divided into two treatment cycles comprising 4–5 days of treatment. The efficacy and safety of CLAD tablets have been verified in randomized controlled clinical trials. Clinical observational studies are performed in more representative populations and over more extended periods, and thus provide valuable complementary insights. Here, we summarize the available evidence for CLAD tablets from post-marketing trials, including two observational, four long-term extensions, and two comparative studies. The patients in the post-marketing setting differed from the cohort recruited in the pivotal phase III trials regarding demographics and MS-related disability. The limited number of studies with small cohorts corroborate the disease-modifying capacity of oral CLAD and report on a durable benefit after active treatment periods. Skin-related adverse events were common in the studies focusing on safety aspects. In addition, single cases of CLAD-associated autoimmune events have been reported. Lastly, CLAD tablets appear safe regarding COVID-19 concerns, and patients mount a robust humoral immune response to SARS-CoV‑2 vaccination. We conclude that the current real-world evidence for CLAD tablets as immune reconstitution therapy for treatment of MS is based on a small number of studies and a population distinct from the cohorts randomized in the pivotal phase III trials. Further research should advance the understanding of long-term disease control after active treatment periods and the mitigation of adverse events.

Outcomes and Toxicities of Modern Combined Modality Therapy with Atezolizumab Plus Bevacizumab and Radiation Therapy for Hepatocellular Carcinoma.

Simple SummaryHepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide with slow progress in the development of effective therapies. The breakthrough IMbrave150 trial established atezolizumab plus bevacizumab as the standard of care first-line therapy for patients with unresectable/advanced HCC, demonstrating improved overall survival. Radiation therapy (RT) is a locoregional treatment that may prevent morbidity from tumor-related vascular compromise and associated liver failure. There is no documented evidence yet describing the safety and outcomes of combination RT and atezolizumab/bevacizumab. In the retrospective review of our experience, we identified 21 patients with advanced HCC who underwent liver-directed RT with atezolizumab/bevacizumab. From our findings, the treatment is well-tolerated, safe, and does not potentiate liver failure. There were uncommon autoimmune or GI bleeding events in some patients, mostly unrelated to RT. Post-RT absolute lymphocyte counts (ALC) improved more quickly with atezolizumab/bevacizumab than they did without, which may be a favorable treatment prognosticator.Atezolizumab plus bevacizumab has become frontline therapy for unresectable HCC. The compatibility of atezolizumab/bevacizumab with liver-directed RT has not been reported. Methods: HCC patients treated with liver-directed RT and atezolizumab/bevacizumab between 1/2020–11/2021 were included. Toxicity and outcomes were retrospectively recorded. For ALCs, we matched the analysis to a previously cohort of RT-treated HCC patients who did not receive atezolizumab/bevacizumab. Survival and time-to-liver-failure were analyzed using Kaplan–Meier. Results: Of 21 patients, with a median follow-up of 9.5 months, the median OS was 16.1 months. Post-RT, all patients had reduced tumors or treatment response. There were no ≥Grade 3 RT-related toxicities. Autoimmune complications occurred in two patients (9.5%), and GI bleeding in three patients (14.3%). Liver function remained stable post-RT. There was a marked decrease in ALCs immediately post-RT (post-RT/pre-RT ratio 47.3%, p < 0.0001), restored by 1 month to pre-treatment baseline (1-month post-RT/pre-RT ratio 95.1%, n.s.). Compared to HCC patients treated with RT alone, post-RT ALC recovery was faster with atezolizumab/bevacizumab (p = 0.009). Conclusion: In this first reported experience of RT with modern systemic therapy for HCC, combination therapy is safe and well-tolerated. As a favorable prognosticator, there appears to be faster recovery of ALC among patients who received RT with atezolizumab/bevacizumab.

Inflammatory demyelinating polyneuropathy after the ChAdOx1 nCoV-19 vaccine may follow a chronic course

BackgroundRare autoimmune neurological events have been reported during the ongoing global drive for mass vaccination as a means of controlling the Covid-19 pandemic. Guillain-Barré syndrome, an acute inflammatory neuropathy well recognised as a rare complication of influenza vaccination, has been reported to follow administration of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. MethodsWe report four patients with inflammatory demyelinating polyneuropathy after vaccination in whom a relapsing or progressive course indicated the development of chronic inflammatory demyelinating polyneuropathy (CIDP). ConclusionsAwareness of this complication and distinction from Guillain-Barré syndrome enables the timely institution of maintenance immunomodulatory treatment. Our report also highlights the likely relationship between vaccination and the subsequent development of CIDP, but definitive demonstration of a causal link needs larger studies.

High Residual β-cell Function in Chinese Patients With Autoimmune Type 1 Diabetes.

The destruction of pancreatic β cells causes type 1 diabetes mellitus (T1D), an autoimmune disease. Studies have demonstrated that there is heterogeneity in residual β-cell function in Caucasians; therefore, we aimed to evaluate β-cell function in Chinese autoimmune T1D patients. β-cell function was determined using oral glucose tolerance testing or standardized steamed bread meal tolerance test in 446 participants with autoantibody-positive T1D. Clinical factors, such as age onset, sex, duration, body mass index, autoantibodies, other autoimmune diseases, diabetic ketoacidosis, hypoglycemia events, glycosylated hemoglobin, and insulin dose, were retrieved. We also analyzed single nucleotide polymorphism (SNP) data for C-peptides from 144 participants enrolled in the Chinese-T1D genome-wide association study. Of 446 T1D patients, 98.5%, 97.4%, 86.9%, and 42.6% of individuals had detectable C-peptide values (≥ 0.003 nmol/L) at durations of < 1 year, 1 to 2 years, 3 to 6 years, and ≥ 7 years, respectively. A total of 60.7% of patients diagnosed at ≥ 18 years old and 15.8% of those diagnosed at < 18 years had detectable C-peptide after ≥ 7 years from the diagnosis. Furthermore, the patients diagnosed at ≥ 18 years old had higher absolute values of stimulated C-peptide (≥ 0.2 nmol/L). Diabetic ketoacidosis, hypoglycemia events, and insulin doses were shown to be associated with β-cell function. SNPs rs1770 and rs55904 were associated with C-peptide levels. Our results have indicated that there are high residuals of β-cell mass in Chinese patients with autoimmune T1D. These findings may aid in the consideration of therapeutic strategies seeking prevention and reversal of β-cell function among Chinese T1D patients.

Catch-up growth of infants born to mothers with autoimmune rheumatic disorders

BackgroundIn women with autoimmune rheumatic disorders (ARD), pregnancy complications or postpartum events are more frequent compared to the general population. Transplacental autoantibodies or cytokines influence various fetal and neonatal outcomes. We compared the growth patterns of babies born to mothers with ARD versus healthy mothers to assess the long-term growth outcomes of children born to women with ARD.MethodsThis was a retrospective age-matched cohort analyses of babies born to mothers with ARD from the hospitals belonging to the Catholic University of Korea between 2010 and 2017. Demographic and autoimmune laboratory test data of the mothers and newborns were assessed. Neonatal growth was measured in terms of height and weight, measured at birth and follow-up examinations.ResultsWe enrolled 142 infants from mothers with ARD and 149 infants from healthy mothers. There was no significant difference between mothers with ARD and healthy mothers in terms of delivery age, parity, abortion, and premature delivery history. The mothers with ARD were diagnosed with systemic lupus erythematosus (81%), Sjogren syndrome (6%), and other autoimmune phenomena (11%). The groups were significantly different in terms of neonatal characteristics such as prematurity, gestational age, birth weight, and height, but not in Apgar score and delivery type. For most neonates, autoimmune laboratory results were normalized within 1 year, except for anti-La/SSB antibody, which remained high in some. The height and weight for age z-score were lower than the normal age groups at birth but showed catch-up growth by 2 years of age.ConclusionsLow birthweight and prematurity at birth for neonates born to mothers with ARD could be caught up by 2 years of age, and maternal ARD does not affect the growth of their offspring.

Endocrine Toxicities of Antineoplastic Therapy: The Adrenal Topic.

Simple SummaryPrimary adrenal insufficiency (PAI) induced by anticancer drugs is a rare occurrence. However, with the expanding use of immune checkpoint inhibitors (ICIs), an increasing number of patients affected by ICI-induced PAI are expected. As a result, oncologists should be aware of the risk of PAI in patients on ICIs (and other anticancer agents) and the related clinical presentations to diagnose this condition early, provide the appropriate treatment, and timely involve endocrinologists in the management of those patients. In parallel, patients on these medications, together with their caregivers and relatives, should receive detailed information about PAI risk and be trained to act appropriately at the onset of alarm symptoms. Large collaborative trials are needed to develop appropriate tests to assess the personal risk of drug induced PAI better and improve its early diagnosis in cancer patients and patients affected by other forms of PAI.Immune checkpoint inhibitors (ICIs) have improved survival in patients affected by several solid tumours at the cost of new autoimmune adverse events. Endocrine toxicity is frequently reported in patients treated with these agents, mainly as thyroid dysfunction and hypophysitis. Primary adrenal insufficiency is reported in 1–2% of patients receiving a single ICI, but its rate is approximately 5% in patients treated with a combination of two ICIs. The clinical presentation of adrenal insufficiency may be insidious due to symptoms that are not specific. The same symptoms in cancer patients are frequently multifactorial, rendering the early diagnosis of adrenal insufficiency challenging in this group of patients. As adrenal insufficiency can be fatal if not rapidly diagnosed and treated, oncologists should be aware of its clinical presentations to timely involve endocrinologists to offer patients the appropriate management. In parallel, it is essential to educate patients, their caregivers, and relatives, providing them with detailed information about the risk of adrenal insufficiency and how to manage alarming symptoms at their onset. Finally, large collaborative trials are needed to develop appropriate tests to assess better the personal risk of drug-induced adrenal insufficiency and its early diagnosis and treatment, not only in cancer patients.

Potential immunological effects of gender-affirming hormone therapy in transgender people - an unexplored area of research.

There are well-described sex-based differences in how the immune system operates. In particular, cisgender (cis) females have a more easily activated immune system; associated with an increased prevalence of autoimmune diseases and adverse events following vaccinations. Conversely, cis males have a higher threshold for immune activation, and are more prone to certain infectious diseases, such as coronavirus disease (COVID-19). Oestrogen and testosterone have immune-modulatory properties, and it is likely that these contribute to the sexual dimorphism of the immune system. There are also important immune-related genes located on the X chromosome, such as toll-like receptor (TLR) 7/8; and the mosaic bi-allelic expression of such genes may contribute to the state of immune hyperactivation in cis females. The scientific literature strongly suggests that sex-based differences in the functioning of the immune system are related to both X-linked genes and immune modulation by sex hormones. However, it is currently not clear how this impacts transgender (trans) people receiving gender-affirming hormonal therapy. Moreover, it is estimated that in Australia, at least 2.3% of adolescents identify as trans and/or gender diverse, and referrals to specialist gender-affirming care are increasing each year. Despite the improving social awareness of trans people, they remain chronically underrepresented in the scientific literature. In addition, a small number of case studies describe new onset autoimmune disorders in adult trans females following oestrogen use. However, there is currently minimal long-term research with an immunological focus on trans people. Therefore, to ensure the positive health outcomes of trans people, it is crucial that the role of sex hormones in immune modulation is investigated further.

Vasculitis induced by biological agents used in rheumatology practice: A systematic review.

Objectives Biological medications have been used with an increasing frequency to treat rheumatological diseases. Autoimmune events can be induced by these drugs, such as psoriasiform lesions, alopecia, lupus and, vasculitis, which more often affects the skin (small-sized vessels) and eventually other organs. In this review, we describe the clinical profile of patients with vasculitis induced by the main biological agents used in rheumatology.Patients and methods We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The PubMed database was used for searching eligible articles. We included case reports, case series, and letter to the editor of patients on anti-tumor necrosis factor-alpha (anti-TNF-a) molecules, as well as tocilizumab, ustekinumab, secukinumab, rituximab, and abatacept, who had vasculitis induced by these agents.Results Eighty-one articles were included for final analysis (n=89). Twenty-seven patients were using infliximab, 20 adalimumab, 18 etanercept, seven secukinumab, four certolizumab, four rituximab, three golimumab, three ustekinumab, two abatacept, and one tocilizumab. Unspecific leukocytoclastic vasculitis (LCV) was the most common type of vasculitis (n=37), followed by anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (n=16). The medication was replaced with another biological molecule in 23 cases, with only four relapses. In six cases, the biological was maintained, but vasculitis worsened/persisted in one case, being necessary drug removal.Conclusion Infections, infusion reaction, cancer, and autoimmune events are well-known side effects of biological therapy. This review demonstrates that vasculitis is another adverse effect of this type of therapy, particularly the anti-TNF-a molecules, and LCV the most reported type of vasculitis.

Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data

Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.

Abstract 12876: Identification of Pathogenic Immune Cell Subsets in Immunotherapy-Induced Myocarditis

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune related adverse events (irAE) such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T-cell-mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in ICI myocarditis are unknown. Hypothesis: We hypothesize that ICI myocarditis is associated with significant quantitative and molecular changes in pathogenic immune cell subsets. Methods: To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry (CyTOF) on peripheral blood mononuclear cells from 40 patients and controls with autoimmune adverse events (irAE) on ICI including four patients with ICI myocarditis. We also profiled 15 patients/controls using single cell T-cell receptor (TCR) sequencing and RNA sequencing (scRNA-seq) with feature barcoding for surface marker expression confirmation. Results: With both methods, we found expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in ICI myocarditis patients compared to controls. Using TCR sequencing, these CD8+ Temra cells were clonally expanded in myocarditis patients. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype with expression of granzyme/perforin. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype two months after treatment with glucocorticoids. Differential expression of proinflammatory chemokines (CCL4/CCL4L2/CCL5) was uncovered in clonally expanded Temra CD8+ cells, and ligand-receptor analysis implicated their regulation of other inflammatory cells such as monocytes and NK cells. Conclusions: Clonal cytotoxic Temra CD8+ cells are significantly increased in patients with ICI myocarditis, and have unique transcriptional changes, including upregulation of chemokines CCL4/CCL4L2/CCL5, which may serve as attractive diagnostic/therapeutic targets.

Pembrolizumab (PEM) Added to ICE Chemotherapy Results in High Complete Metabolic Response Rates in Relapsed/Refractory Classic Hodgkin Lymphoma (cHL): A Multi-Institutional Phase II Trial

Pembrolizumab (PEM) Added to ICE Chemotherapy Results in High Complete Metabolic Response Rates in Relapsed/Refractory Classic Hodgkin Lymphoma (cHL): A Multi-Institutional Phase II Trial

Alemtuzumab-induced autoimmune thyroid events in patients with relapsing-remitting multiple sclerosis: A real-life and monocentric experience at a tertiary-level centre.

Alemtuzumab-induced autoimmune thyroid events (AIATEs) are the most common adverse effects observed in relapsing-remitting multiple sclerosis (RRMS) patients. This study aims to explore the clinical and biochemical characteristics of such AIATEs, and to examine the risk factors for their occurrence, particularly for the worst clinical phenotype of fluctuating Graves' disease (GD). We retrospectively analysed a real-life single-centre consecutive series of 57 RRMS patients treated with alemtuzumab whose clinical and biochemical parameters were collected before starting the treatment and then monthly during their follow-up. AIATEs developed in 39% of patients a mean 17 months ± 11 after the first cycle of alemtuzumab. The most common AIATEs were GD (64%), followed by Hashimoto's thyroiditis with hypothyroidism (23%), TSH-receptor-antibody (TRAb)-positive hypothyroidism (9%), and silent thyroiditis (4%). GD showed a fluctuating course in 57% of cases. Baseline positivity for anti-thyroperoxidase antibodies, and higher absolute titers of anti-thyroglobulin and anti-thyroperoxidase antibodies correlated significantly with the risk of developing AIATEs, but TRAb positivity did not. Higher TRAb titers at the time of GD being diagnosed correlated strongly with a greater risk of the fluctuating GD phenotype. On ROC curve analysis, we found that a cut-off of 7.3 IU/L could be used to predict the risk of developing a fluctuating GD, with a positive predictive value of 100%. TRAb levels measured with commercial automatic methods at the time of a patient being diagnosed with alemtuzumab-induced GD emerged as a novel biomarker for predicting a fluctuating disease phenotype, with an influence on subsequent therapeutic decisions and patients' follow-up.

IgG4-related autoimmune manifestations in Alemtuzumab-treated multiple sclerosis patients

We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab.

Prospective Phase II Trial of Radiation Therapy in Localized Non-Gastric Marginal Zone Lymphoma With Evaluation of Autoimmunity and Helicobacter Pylori Status

This phase 2 multicenter clinical trial evaluated the effectiveness and safety of radiotherapy in localized non-gastric marginal zone lymphoma (MZL) and assessed the prevalence of markers of autoimmunity and Helicobacter pylori (HP) infection in this population. It was designed to test the hypotheses that-long term local progression-free survival (PFS) would be > 80% and that death within 10 years would occur in < 10% of patients.Eligibility required untreated stage I-II, or bilateral paired-organ confined (e.g., bilateral conjunctival), non-gastric MZL. CT scanning, bone marrow biopsy, autoantibody serology panel and HP evaluation by urease breath test or endoscopy were mandatory. Involved-field or involved-site, conventionally-fractionated radiotherapy was delivered to 30-30.6 Gy, except for orbital MZL which received 24-25 Gy. Patients with detected HP infections additionally received eradication therapy.Between 2006 and 2014, six centers enrolled 70 patients, 68 of whom commenced protocol treatment. Median age was 59 (range: 23-84) years and 31 (46%) were male. Stage was I n = 55, II n = 9 and paired-organ confined n = 4. Involved extranodal sites with ≥ 3 cases were orbital n = 18, conjunctiva n = 13, lacrimal n = 8, skin n = 8, salivary n = 7, muscle n = 3. Four patients had primary nodal MZL and 14 (21%) patients were PET-staged. With a median follow-up of 5 years (range 0.7-9.4), 5-year progression-free and overall survival rates were 79% and 95% respectively. One lymphoma-related death and 2 in-field failures (after 25 and 30 Gy respectively) occurred. Distant relapse sites were skin (n = 2), lymph nodes (n = 2) duodenum, stomach, skeletal muscle and conjunctiva (1 each). No patient with bilateral paired-organ MZL relapsed. Apart from cataracts (n = 18), 6 grade 3 late adverse events occurred (3 treatment-related). Two grade 4 late events (nephrotic syndrome and thrombosis) were treatment-unrelated. Autoantibodies or auto-immune events were detected in 26 of 68 (38%) patients. HP infection was detected (and treated) in 15 of 63 patients tested (24%). Neither autoimmunity nor HP was detected in 27/68 (40%) patients.Radiotherapy was a highly-effective, potentially-curative treatment with low toxicity in localized non-gastric MZL. Autoimmunity, HP infection or both were detected in 60% of patients.

Immune checkpoint inhibitor-associated cardiotoxicity detected by 68Ga-DOTATATE PET/CT and 68Ga-FAPI PET/CT.

The growing clinical use of immune checkpoint inhibitors (ICIs) has made significant progress in the treatment of various subsets of tumours. Nonetheless, potential cardiotoxicity and autoimmune adverse events with ICI were considered. Multiple cardiac molecular injuries induced by ICIs had not been well investigated. A 75-year-old male with advanced upper tract urothelial carcinoma was treated with, and subsequently presented fatigue and dyspnoea, palpitations, myalgia, as well as intermittent coughing sputum and dizziness in 2 weeks. Computed tomographic angiography (CTA) examination showed mild stenosis on the left main coronary artery. Cardiac magnetic resonance (CMR) recognized abnormal ventricular motion with corresponding left ventricular ejection fraction (LVEF) 46%, end-diastolic volume (EVD) of 106.4 mL, but absent evidential cardiomyopathy features, echo examination indicated left ventricular (LV) hypertrophy coupled with severe cardiac dysfunction (ejection fraction (EF) 38%). NT-proBNP of 4140 pg/mL cTnl of 125.8 pg/mL were recorded. Somatostatin Subtype Receptor 2 (SST2) imaging by Ga-68...

Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

ObjectiveTo explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment.MethodsMulticenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases.ResultsTwenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058).ConclusionsA PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.​

MYOSITIS AND RESPIRATORY FAILURE WITH PEMBROLIZUMAB

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pembrolizumab, an anti-programmed death 1 receptor monoclonal antibody, increases survival in non-small cell lung cancer (NSCLC). It causes less toxicity than traditional chemotherapy, however it can induce autoimmune adverse events including pneumonitis and colitis. There have been a limited number of case reports chronicling myositis with respiratory distress as an adverse effect of pembrolizumab. We present a case of a patient with NSCLC being treated with pembrolizumab, which induced respiratory failure secondary to myositis. CASE PRESENTATION: A 77-year-old man with metastatic NSCLC status post right upper lobectomy on carboplatin/paclitaxel/pembrolizumab started 10/26/20, with recent hepatitis diagnosed one week prior to admission and identified as secondary to pembrolizumab, on treatment with prednisone (1 mg/kg), presented with proximal weakness and progressive exertional dyspnea over the last three weeks. Vital signs were remarkable for tachypnea and tachycardia. Physical exam showed 2/5 proximal muscle strength in upper and lower extremities, absent deep tendon reflexes, and no skin rash. Labs revealed CK 1567, LDH 889, SARS-CoV2 PCR negative. CT pulmonary arteries was negative for acute lung processes. The patient required noninvasive positive pressure ventilation (NIPPV) for respiratory distress. Treatment was initiated with pyridostigmine (60mg QID PO) and pulsed glucocorticoids (methylprednisolone 1 g daily). He remained NIPPV dependent so pyridostigmine was increased to 90mg QID PO and IV immunoglobulin (IVIG) 85 g QD was added for refractory respiratory failure and muscle weakness. Acetylcholine receptor antibodies, ANA, anti SSA/SSB, anti-Jo1 were negative. Lumbar puncture was performed with normal opening pressure, CSF cell count, and chemistry. The clinical diagnosis was myositis attributed to pembrolizumab. The patient responded to a week of continued IVIG (30 g QD for 5 more days) and tapering steroids, with improvement in proximal muscle strength and was weaned off NIPPV. DISCUSSION: Pembrolizumab works as an immune checkpoint inhibitor, which may cause an autoimmune effect. One study identified 5 patients with pembrolizumab induced myositis. Our patient, presented with proximal muscle weakness and respiratory distress requiring NIPPV, two months after starting pembrolizumab. His respiratory distress was not due to lung disease. Autoimmune workup was negative. He underwent a lumbar puncture which ruled out Guillain-Barre syndrome. He was diagnosed with pembrolizumab induced myositis. A limitation in our case was that a biopsy never confirmed the diagnosis as he responded to pulsed steroids and IVIG. In other cases, the myositis has been treated by plasma exchange or immunosuppression. CONCLUSIONS: Pembrolizumab can induce potentially fatal myositis. It is crucial that clinicians are aware of this so prompt treatment can be initiated. REFERENCE #1: Claus J, Van Den Bergh A, Verbeek S, Wauters E, Nackaerts K. Pembrolizumab-induced necrotizing myositis in a patient with metastatic non-small-cell lung cancer: a case report. Lung Cancer Manag. 2019 May 8;8(2):LMT10. doi: 10.2217/lmt-2018-0017. PMID: 31645893;PMCID: PMC6802710. REFERENCE #2: Liewluck T, Kao JC, Mauermann ML. PD-1 Inhibitor-associated Myopathies: Emerging Immune-mediated Myopathies. J Immunother. 2018 May;41(4):208-211. doi: 10.1097/CJI.0000000000000196. PMID: 29200081. REFERENCE #3: Robinson SD, Lai C, Hotton G, Anand G. Life threatening pembrolizumabinduced myositis in a patient treated for advanced adenocarcinoma of the lung. Acute Med. 2019;18(3):197-199. PMID: 31536059. DISCLOSURES: No relevant relationships by Shlomo Greenberg, source=Web Response No relevant relationships by Daniel Kurbanov, source=Web Response No relevant relationships by Visala Natarajan, source=Web Response

The Germinal Center Milieu in Rheumatoid Arthritis: The Immunological Drummer or Dancer?

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, affecting approximately 1% of the general population. To alleviate symptoms and ameliorate joint damage, chronic use of immunosuppressives is needed. However, these treatments are only partially effective and may lead to unwanted side effects. Therefore, a more profound understanding of the pathophysiology might lead to more effective therapies, or better still, a cure. The presence of autoantibodies in RA indicates that B cells might have a pivotal role in the disease. This concept is further supported by the fact that a diverse antibody response to various arthritis-related epitopes is associated with arthritis development. In this context, attention has focused in recent years on the role of Germinal Centers (GCs) in RA. Since GCs act as the main anatomic location of somatic hypermutations, and, thus, contributing to the diversity and specificity of (auto) antibodies, it has been speculated that defects in germinal center reactions might be crucial in the initiation and maintenance of auto-immune events. In this paper, we discuss current evidence that various processes within GCs can result in the aberrant production of B cells that possess autoreactive properties and might result in the production of RA related autoantibodies. Secondly, we discuss various (pre-)clinical studies that have targeted various GC processes as novel therapies for RA treatment.

Hematologic Autoimmune Manifestation Secondary to Coronavirus Disease 19 Infection – A Single-Center Experience

Introduction: Since December 2019, multiple human cases of novel coronavirus infection were reported, representing with upper respiratory symptoms (influenza-like presentation). The virus was named the Severe acute respiratory system coronavirus 2 (SARS-COV-2). Studies have reported cases of patients with COVID-19 infection, including development of several autoimmune events that suggests that infection with SARS CoV-2 may be associated with initiation of autoimmune hematological autoimmune disorders.&#x0D; Aim: Review the hematological autoimmune phenomenon after infection with SARS-COV-2 in order to assist into the pathogenic mechanisms, clinical manifestations and treatment of this group of patients. &#x0D; Materials and methods: This is a retrospective study that includes 21 patients with autoimmune diseases like secondary immune thrombocytopenia (ITP), autoimmune hemolytic anemia( AIHA) and thrombotic thrombocytopenic purpura (TTP) that have emerged after COVID-19 infection. The patients were diagnosed and treated at the University Clinic of Hematology for a period of time from January 2020 to April 2021.&#x0D; Results: The most common hematologic autoimmune disorder was ITP in 13 cases (62%) followed by AIHA in 5 cases (24%) and TTP in 3 individuals (14%). The mean time of onset of the hematologic auto-immune presentations was 18,4 ± 10,3 days. The therapy of this conditions in patients with COVID-19 infection requires an individualized approach to achieve a precise balance between the risk of severe bleeding and of thromboembolic events. &#x0D; Conclusion: Causal relationship between COVID-19 infection and these autoimmune events still requires further studies. We should all have in mind the risk of development of hematologic autoimmune disorders in infected patients.