Autoimmune Flares Research Articles

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases.

Migration of immune cells to sites of inflammation is a critical step in the body's response to infections but also during autoimmune flares. Chemokine receptors, members of the GPCR receptors, are instrumental in directing specific cell types to their target organs. Herein, we describe a highly potent small molecule antagonist of the chemokine receptor CCR6, which came out of fine-tuned structural elaborations from a proprietary HTS hit. Three main issues in the parent chemical series-cytotoxicity, phototoxicity, and hERG, were successfully solved. Biological characterization demonstrated that compound 45 (IDOR-1117-2520) is a selective and insurmountable antagonist of CCR6. In vivo proof-of-mechanism studies in a mouse lung inflammation model using a representative compound from the chemical class of 45 confirmed that the targeted CCR6+ cells were efficiently inhibited from migrating into the bronchoalveoli. Finally, ADMET and physicochemical properties were well balanced and the preclinical package warranted progress in the clinic.

Excitable dynamics of flares and relapses in autoimmune diseases

Many autoimmune disorders exhibit flares in which symptoms erupt and then decline, as exemplified by multiple sclerosis (MS) in its relapsing-remitting form. Existing mathematical models of autoimmune flares often assume regular oscillations, failing to capture the stochastic and non-periodic nature of flare-ups. We suggest that autoimmune flares are driven by excitable dynamics triggered by stochastic events auch as stress, infection and other factors. Our minimal model, involving autoreactive and regulatory T-cells, demonstrates this concept. Autoimmune response initiates antigen-induced expansion through positive feedback, while regulatory cells counter the autoreactive cells through negative feedback. The model explains the decrease in MS relapses during pregnancy and the subsequent surge postpartum,based on lymphocyte dynamics. Additionally, it identifies potential therapeutic targets, predicting significant reduction in relapse rate from mild adjustments of regulatory Tcell activity or production. These findings indicate that excitable dynamics may underlie flare-ups across various autoimmune disorders, potentially informing treatment strategies.

Safety and Efficacy of Immune Checkpoint Inhibitors in Cancer Patients and Preexisting Autoimmune Disease: A Systematic Review and Meta-Analysis in Non–Small-Cell Lung Cancer

Cancer patients with preexisting autoimmune diseases (AID) have been traditionally excluded from clinical trials of immune checkpoint inhibitors (ICI) due to concerns for toxicity. As indications for ICI expand, more data are needed on the safety and efficacy of ICI treatment in cancer patients with AID. We systematically searched for studies consisting of NSCLC, AID, ICI, treatment response, and adverse events. Outcomes of interest include incidence of autoimmune flare, irAE, response rate, and ICI discontinuation. Study data were pooled using random-effects meta-analysis. Data were extracted from 24 cohort studies, consisting of 11,567 cancer patients (3774 NSCLC patients and 1157 with AID). Pooled analysis revealed an AID flare incidence of 36% (95% CI, 27%-46%) in all cancers and 23% (95% CI, 9%-40%) in NSCLC. Preexisting AID was associated with an increased risk of de novo irAE in all cancer patients (RR 1.38, 95% CI, 1.16-1.65) and NSCLC patients (RR 1.51, 95% CI, 1.12-2.03). There was no difference in de novo grade 3 to 4 irAE and tumor response between cancer patients with and without AID. However, in NSCLC patients, preexisting AID was associated with a 2-fold increased risk of de novo grade 3 to 4 irAE (RR 1.95, 95% CI, 1.01-3.75) but also better tumor response in achieving a complete or partial response (RR 1.56, 95% CI, 1.19-2.04). NSCLC patients with AID are at a higher risk of grade 3 to 4 irAE but are more likely to achieve treatment response. Prospective studies focused on optimizing immunotherapeutic strategies are needed to improve outcomes for NSCLC patients with AID.

Epidemiology of liver failure in Asia-Pacific region.

The global burden of deaths caused by liver failure is substantial. The Asia-Pacific region is home to more than half of the global population and accounted for 62.6% of global deaths because of liver diseases in 2015. The aetiology of liver failure varies in different countries at different times. Viruses (Hepatitis A, B and E), drugs (herbs and anti-tuberculous drugs), toxins (alcohol use) and autoimmune flares are mainly responsible of majority of liver failure in individuals with normal liver (acute liver failure; ALF); else these may precipitate liver failure in those with chronic liver disease (acute-on-chronic liver failure; ACLF). Concomitant increases in alcohol misuse and metabolic syndrome in recent years are concerning. Ongoing efforts to address liver failure-related morbidity and mortality require accurate contemporary estimates of epidemiology and outcomes. In light of the ever-changing nature of liver disease epidemiology, accurate estimates for the burden of liver failure across the countries are vital for setting clinical, research and policy priorities. In this review, we aimed to describe the current as well as changing epidemiological trends of common liver failure syndromes, ALF and ACLF in the Asia-Pacific region.

SEOM-GECP-GETTHI Clinical Guidelines for the treatment of patients with thymic epithelial tumours (2021)

Thymic epithelial tumours (TET) represent a heterogeneous group of rare malignancies that include thymomas and thymic carcinoma. Treatment of TET is based on the resectability of the tumour. If this is considered achievable upfront, surgical resection is the cornerstone of treatment. Platinum-based chemotherapy is the standard regimen for advanced TET. Due to the rarity of this disease, treatment decisions should be discussed in specific multidisciplinary tumour boards, and there are few prospective clinical studies with new strategies. However, several pathways involved in TET have been explored as potential targets for new therapies in previously treated patients, such as multi-tyrosine kinase inhibitors with antiangiogenic properties and immune checkpoint inhibitors (ICI). One third of patient with thymoma present an autoimmune disorders, increasing the risk of immune-related adverse events and autoimmune flares under ICIs. In these guidelines, we summarize the current evidence for the therapeutic approach in patients with TET and define levels of evidence for these decisions.

Acceptability of the COVID-19 vaccine among patients with chronic rheumatic diseases and health-care professionals: a cross-sectional study in 19 Arab countries.

Acceptability of the COVID-19 vaccine among patients with chronic rheumatic diseases and health-care professionals: a cross-sectional study in 19 Arab countries.

Histologic Changes in Core-Needle Liver Biopsies From Patients With Acute-on-Chronic Liver Failure and Independent Histologic Predictors of 28-Day Mortality.

The histologic features in patients with acute-on-chronic liver failure (ACLF) are evolving, and histologic indicators of patients' poor prognosis are not yet fully established. To evaluate the independent histologic predictors of 28-day mortality in ACLF patients on core-needle liver biopsies. Core-needle biopsies from patients with a diagnosis of ACLF (n = 152) as per the European Association for the Study of the Liver criteria were included during 8 years. Liver biopsies from 98 patients with compensated chronic liver disease were included as disease controls for histologic comparison. Features of ongoing changes, such as hepatic necrosis, hepatic apoptosis, cholestasis, hepatocyte degeneration, bile ductular proliferation, Mallory-Denk bodies, steatosis, and extent of liver fibrosis, were analyzed for predicting short-term mortality (28 days). A P value of <.05 was considered significant. In our cohort of ACLF patients, the following etiologies for acute decompensation were identified: alcohol, 47 of 152 (30.9%); sepsis, 24 of 152 (15.7%); hepatotropic viruses, 20 of 152 (13.1%); drug-induced liver injury, 11 of 152 (7.2%); autoimmune flare, 9 of 152 (5.9%); mixed etiologies, 5 of 152 (3.2%); and cryptogenic, 36 of 152 (23.6%). On histologic examination, hepatic necrosis (P < .001), dense lobular inflammation (P = .03), cholestasis (P < .001), ductular reaction (P = .001), hepatocyte degeneration (P < .001), and absence of advanced fibrosis stages (P < .001) were identified significantly more othen in ACLF patients than in disease controls on univariate analysis. On multivariate Cox regression analysis, the absence of advanced Ishak histologic activity index fibrosis stages (P = .02) and the presence of dense lobular inflammation (P = .04) were associated with increased 28-day mortality in ACLF patients. After adjusting the clinical causes of acute decompensation, only dense lobular inflammation was found as an independent predictor of short-term mortality (P = .04) in ACLF patients. Dense lobular necroinflammatory activity is a clinically independent histologic predictor of 28-day short-term mortality in patients with ACLF.

Tolerability of Coronavirus Disease 2019 Vaccines, BNT162b2 and mRNA-1273, in Patients With Thymic Epithelial Tumors

IntroductionDefects in immunologic self-tolerance result in an increased risk for development of paraneoplastic autoimmune diseases (ADs) and immune-mediated toxicity in response to immune stimulation in individuals with thymic epithelial tumors (TETs). We conducted a survey to evaluate the tolerability of coronavirus disease 2019 (COVID-19) mRNA vaccines in patients with TETs, including individuals with preexisting AD. MethodsAfter reviewing published data on adverse events associated with the BNT162b2 (Pfizer, Inc., and BioNTech) and mRNA-1273 (ModernaTX, Inc.) mRNA vaccines, we designed and administered a questionnaire to participants at the following three time points: after each dose of vaccination and 1 month after the final dose. Questions related to AD and use of immunosuppressive drugs were included. Descriptive statistics were used to analyze data, and results were compared with previously described results related to the BNT162b2 and mRNA-1273 vaccines. ResultsFrom February 26 to June 1, 2021, we administered the survey to 54 participants (median age = 58 y, thymoma = 33, preexisting AD = 19). Common adverse events included injection site pain, fatigue, and headaches. There were no vaccination-related hospitalizations or deaths. Autoimmune flares occurred in three patients (16%) after the first dose and three patients (17%) after the second dose. Most AD flares were mild and self-limited. One patient (2%) was diagnosed with having a new AD after vaccination. ConclusionsTolerability of COVID-19 mRNA vaccines in patients with TETs is comparable to the general population. Most patients with preexisting AD did not experience disease flares, and the development of new AD was rare. Patients with TETs should be encouraged to get vaccinated against COVID-19 owing to the documented benefits of vaccination and manageable risk profile.

Clinical and peculiar immunological manifestations of SARS-CoV-2 infection in systemic lupus erythematosus patients.

ObjectivesThe impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with systemic lupus erythematosus (SLE) remains unclear and data on clinical manifestations after infection are lacking. The aim of this multicentre study is to describe the effect of SARS-CoV-2 in SLE patients.MethodsSLE patients referring to 4 Italian centres were monitored between February 2020 and March 2021. All patients with SARS-CoV-2 infection were included. Disease characteristics, treatment, disease activity, and SARS-CoV-2 related symptoms were recorded before and after the infection.ResultsFifty-one (6.14%) SLE patients were included among 830 regularly followed-up. Nine (17.6%) had an asymptomatic infection. Five (9.8%), out of 42 (82.6%) symptomatic, developed interstitial pneumonia (no identified risk factor). The presence of SLE major organ involvement (particularly renal involvement) was associated with asymptomatic SARS-CoV-2 infection (p-value = 0.02). Chronic corticosteroid therapy was found to be associated with asymptomatic infection (p-value = 0.018). Three SLE flares (5.9%) were developed after SARS-CoV-2 infection: one of them was characterized by MPO-ANCA positive pauci-immune crescentic necrotizing glomerulonephritis and granulomatous pneumonia.ConclusionsSARS-CoV-2 infection determined autoimmune flares in a small number of our patients. Our data seem to confirm that there was not an increased risk of SARS-CoV-2 in SLE. Patients with asymptomatic SARS-CoV-2 infections were those having major SLE organ involvement. This may be explained by the high doses of corticosteroids and immunosuppressive agents used for SLE treatment.

Association of pre-existing autoimmune diseases in melanoma patients receiving immune checkpoint inhibition with improved survival and increased toxicity.

e21586 Background: Immune checkpoint inhibition (ICI) improves progression-free (PFS) and overall survival (OS) for patients with metastatic melanoma (MM), but induces immune-related adverse events (irAEs). Pre-existing autoimmune disease (pre-AI) is considered a relative contraindication due to concerns of inciting autoimmune flare. We here tested the impact of pre-AI on both the survival and irAEs in MM patients treated with ICI. Methods: We examined MM patients treated with ICI who were enrolled in a clinicopathological database at NYULH with protocol-driven prospective follow up. We compiled a comprehensive list of 23 autoimmune diseases and examined the presence of these diseases prior to ICI treatment. We tested the associations between pre-AI and PFS, OS, and irAEs both in univariate and multivariate models. Results: 74/485 (15.3%) patients, who received 718 lines of ICI treatment as either standard of care or in clinical trials, had pre-AI, most commonly asthma (n=42), inflammatory bowel disease (n=9), psoriasis (n=9), rheumatoid arthritis (n=7), and eczema (n=6). In patients receiving ICI as standard of care (n=535), pre-AI was associated with irAEs (P=0.05) as well as with significantly improved PFS (P=0.024) and OS (P=0.007), controlling for patients’ sex, age, stage, ECOG status, and treatment line (1st line versus 2nd or 3rd line). However, no associations were observed between pre-AI and PFS (P=0.2) or irAEs (P=0.54) in the clinical trial group. Conclusions: Our data demonstrate the disparate impact of pre-AI on response and irAEs in standard of care versus the highly controlled clinical trial settings, and underscore the importance of examining the complex interaction between autoimmune disease before and after initiation of ICI. Our data also challenge the notion that clinicians should avoid use of ICI in pre-AI patients. More mechanistic research is needed to understand how to uncouple ICI response from toxicity.

Loeffler's Endocarditis Treated with Total Artificial Heart as Bridge to Transplant

<h3>Introduction</h3> We report a case of end-stage Loeffler's endocarditis treated with a total artificial heart as a bridge to transplant. <h3>Case Report</h3> A 34 year old man presented with abdominal distention and weight gain. Multimodality imaging showed near obliteration of the left ventricular cavity in systole with a dilated atria, severe atrioventricular valve regurgitation, and right ventricular dysfunction (Figure A-C). These findings led to the diagnosis of Loeffler's endocarditis (eosinophilic myocarditis) in the setting of eosinophilic granulomatosis with polyangiitis (EGPA). He was treated with diuretics and remained stable for two years before presenting with recurrent weight gain and acute kidney injury with congestive hepatopathy. There was no serologic evidence of autoimmune flare and recent positron emission tomography (PET) imaging showed minimal evidence of active inflammation in the heart. Right heart catheterization revealed elevated right sided filling pressures and severely reduced cardiac output. Given the restrictive nature of his disease, use of diuretics resulted in worsening cardiac output and there was a marginal response to inotropes such that his liver and renal function could not be normalized. Endomyocardial resection and direct transplantation were not options given ongoing liver and renal dysfunction, which put him at prohibitive risk of post-operative fulminant end-organ failure. The patient underwent successful placement of a total artificial heart (TAH; SynCardia Systems, LLC) as a bridge to transplantation. Gross pathology revealed severe endomyocardial fibrosis (D-E). His liver and renal function have normalized and the patient is awaiting heart transplant. <h3>Summary</h3> End-stage Loeffler's endocarditis is a disease with high annual mortality for which medical therapy is insufficient and use of a total artificial heart as a bridge to transplant is a viable option as life-saving therapy.

UVB light exposure promotes IgE autoantibody production and skin autoreactivity in mice that express a lupus-associated isoform of Foxp3

Abstract Foxp3 activity is required for the maintenance of self-tolerance, but humans encode an additional exon 2-deficient splice variant isoform of FOXP3 with no known function. To determine how exon 2 of FOXP3 contributes to Treg activity, we generated mice that express exon 2-deficient FoxP3 (called B6.FoxP3ΔExon2). B6.FoxP3ΔExon2 mice develop mild autoimmunity (splenomegaly, autoantibodies and kidney nephritis) with significantly elevated titers of skin-reactive IgE. We also observed skin-reactive IgE antibodies in SLE patients with active photosensitivity, so we challenged B6 and B6.FoxP3ΔExon2 mouse skin with ultraviolet B (UVB) light to determine if UVB damage can induce skin-reactive IgE production. When compared to B6 controls, B6.FoxP3ΔExon2 mice developed greater skin inflammation with increased infiltration of Tregs (CD4+Foxp3+), effector T cells (CD4+CD44+Foxp3−) and IgE+ plasma cells (B220lowCD138+Blimp1+) at the site of UVB damage. B6.FoxP3ΔExon2 mice also had higher numbers of IgE+ antibody-forming cells, IL4-producing T cells (CD4+CD44+Foxp3−) and IgE-producing B cells, but lower numbers of CTLA4+ Tregs in draining lymph nodes from UVB-treated skin. Finally, UVB-treated B6.FoxP3ΔExon2 mice also had worsened kidney disease, phenocopying multi-systemic flares that occur in SLE patients with photosensitivity. Collectively, we found that exon 2 of the Foxp3 gene is required to control UVB-induced cutaneous inflammation though the regulation of type 2 immune activation and skin-reactive IgE. Thus, our findings suggest that photosensitivity reactions in SLE patients may be mediated by altered Foxp3 activity and skin-reactive IgE that could be therapeutically targeted to control systemic autoimmune flares.

Pre-Existing and Treatment-Emergent Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukemia Treated with Targeted Drugs

Pre-Existing and Treatment-Emergent Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukemia Treated with Targeted Drugs

MTE12.01 Is IO an Option for Patients with Contraindications (Auto-immune Disease, Pulmonary Fibrosis, HIV, Hepatitis, Transplant etc)

MTE12.01 Is IO an Option for Patients with Contraindications (Auto-immune Disease, Pulmonary Fibrosis, HIV, Hepatitis, Transplant etc)

Thromboangiitis obliterans episode: autoimmune flare-up or reinfection?

BackgroundThe possible role of infectious pathogens in the development of thromboangiitis obliterans (TAO) was considered soon after the disease was first described. However, it is not yet known whether infectious pathogens induce thrombotic vasculitis or if they cause a type of autoimmune disease. To investigate whether TAO relapses are more likely due to reinfection or autoimmune flare, the serum levels of toll-like receptor (sTLR) 4, sTLR2, C-reactive protein (CRP), and neopterin were evaluated in TAO patients during both the acute and quiescent phases of the disease as well as in a gender-, age-, and smoking habit-matched control group.MethodsFollowing a cross-sectional study design, 28 patients in the acute phase of TAO and 23 patients in the quiescent phase participated in this study. In addition, 31 matched controls were enrolled.ResultsToll-like receptor (TLR) 4 was significantly higher in patients in the acute phase of the disease than in patients in the quiescent phase (P=0.012). Also, TLR4 was significantly higher in the patients with CRP >7 µm/mL than in the patients with lower CRP (P=0.031). Notably, TLR4 in the patients in the quiescent phase of TAO was significantly lower than in the controls (P=0.006). No significant difference in the level of TLR2 was found among the groups (P>0.05). Neopterin was significantly higher in the acute phase of TAO in comparison to the quiescent phase (P=0.003) and the controls (P=0.005).ConclusionThese findings indicate that the trigger of TAO might be Gram-negative bacteria, which can be hidden or immunologically suppressed in the quiescent phase of TAO, leading to a lower level of TLR4 accompanying the normal level of neopterin. However, relapses might develop according to toxic or hypoxic cell injuries. Hence, TLR4 shedding will increase, and therefore, sTLR4 could become closer to the level demonstrated in the controls.

Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders.

Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. Ipilimumab therapy. Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring.

Autoimmune flares. The hows, whens, and whys of killing

Autoimmune flares. The hows, whens, and whys of killing

Autoimmune flares. The hows, whens, and whys of killing

Autoimmune flares. The hows, whens, and whys of killing

Rituximab in the Treatment of Adults with Chronic Idiopathic Thrombocytopenic Purpura (ITP) and Autoimmune Hemolytic Anemia (AIHA).

Corticosteroids have been the first line of treatment of ITP since 1950, however some patients do not respond to this treatment (refractory) and some will relapse after its discontinuation. For such patients second line treatments were introduced. Some patients will continue to be refractory to this treatment and need other therapy modality.Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen exposing B Lymphocytes, causing its depletion. This could alter the production of auto-antibodies in some Auto-Immune diseases and thus could be used in their treatment. Few medical centers had reported using Rituximab in the treatment of refractory (ITP) and (AIHA), yet its definite role could not be determined, and here we share our experience.Patients with documented diagnosis of ITP or AIHA who were refractory to at least two lines of therapy including steroids were offered to receive Rituximab (375mg/m2 weekly for 4 weeks). 15 patients were enrolled, 10 with ITP, 4 with AIHA, 1 with Coombs negative Hemolytic anemia, and 1 with pure red cell aplasia. One had both ITP and AIHA. 10 were females and 5 males. 5 were >60 years old and 10 were < 60 years old. 2 out of the 10 patients with ITP had also Chronic Lymphocytic Leukemia (CLL). Duration of follow up ranged from 2 months to 17 months (average 7 mos). Of the 10 patients with refractory ITP treated with Rituximab overall response was 60%. 4 were NR (no response), 2 were MR (minimal response: Platelets increased to <50000), 2 were PR (Partial response: Platelets increased to <100000) and 2 were complete response (Platelets became normal). 3 patients of 6 with Hemolytic anemia or PRC aplasia had NR, 1 had MR (Hct <30), and 2 had partial response (Hct 30–35). No complete response was observed in this group. In 3 patients with hemolytic anemia and CLL 1 had MR, 1 had PR and 1 had NR. 2 patients with hemolytic anemia who had NR died as a complication of their disease (one with septic shock and one with severe autoimmune flare up). Only one patient with refractory ITP had mild allergic side effects and did not complete 4 doses. No Rituximab related mortality was observed.CONCLUSION:Rituximab therapy had a variable but valuable effect in the treatment of patients with chronic refractory ITP and refractory/ relapsed AIHA. Overall response in our group reached 60%. No clinical or laboratory parameters were found to predict response, although there was a suggestion that males, younger age, and no history of splenectomy have a better chance of response. As we lack an effective alternative treatment in chronic refractory ITP and AIHA, Rituximab use could be a valid option in view of its mild toxicity. Further follow up of our patients and input from other institutions in this regard are needed.