History Of Autoimmune Disease Research Articles

Risk and predictors of ipilimumab-associated cardiac adverse events among patients treated for melanoma: A national cohort analysis.

e14592 Background: Ipilimumab is a CTLA-4 inhibitor widely used to treat advanced melanoma. While ipilimumab-induced cardiac immune-related adverse events (irAE) have been reported, there is a paucity of data from large cohorts. We investigated the risk and predictors of ipilimumab-associated cardiac irAE in a national cohort of patients with cutaneous melanoma. Methods: Using SEER-Medicare linked data, we compared the risk of cardiac irAE between patients treated with ipilimumab with or without concomitant treatment for cutaneous melanoma and controls not treated with ipilimumab following a primary diagnosis of cutaneous melanoma. We excluded patients ≤65 years and patients with cardiac comorbidities diagnosed within one year prior to the initiation of melanoma treatment. The primary endpoint was the incidence of at least one cardiac irAE after ipilimumab initiation including acute pericarditis, myocarditis, cardiomyopathy, conduction disorders, cardiac dysthymias, acute heart failure, and takotsubo syndrome. To estimate the risk of cardiac irAE, we conducted a multivariable competing-risk analysis adjusting for death of any cause within one year of treatment as a competing event. Then, we constructed a stepwise logistic regression to assess the predictors of having at least one cardiac irAE within one year of ipilimumab initiation. Subgroup analysis was conducted among patients who received ipilimumab only. The models were adjusted for patient demographics, disease stage, Charlson comorbidity index (CCI), history of hypertension, autoimmune disease, end stage renal disease (ESRD), chronic anticoagulant, and steroid use. Results: The cohort included 715 patients treated with ipilimumab and 22,070 controls. In the ipilimumab arm, 23.4% had metastatic disease, 9.5% had a history of autoimmune disease, and 2.2% had CCI≥2. The incidence rates of cardiac irAE among patients who received ipilimumab and among the control group were 23.3 and 13.6 per 1,000 person-years, respectively. We found that patients who received ipilimumab had a higher risk of cardiac irAE compared to controls (adjusted hazard ratio 1.87; 95%CI 1.50-2.32; p < 0.001). In addition to ipilimumab treatment, other predictors of cardiac irAE included male gender, older age, patients with metastatic disease, history of autoimmune disease, hypertension, ESRD, anticoagulant use, and CCI≥2. The predictors of cardiac irAE were also consistent in the subgroup analysis of patients who received ipilimumab only. Conclusions: Patients who received ipilimumab with or without concomitant treatment for cutaneous melanoma had a higher risk for cardiac irAE. Predictors of cardiac irAE help tailor therapy according to patients’ risk profiles.

GALLANT: A phase 2 study using metronomic gemcitabine, doxorubicin, nivolumab, and docetaxel as second/third-line therapy for advanced sarcoma (NCT04535713).

11518 Background: In our experience, combinatorial therapy with lower doses of doxorubicin, gemcitabine, and docetaxel has been effective with a manageable toxicity profile in patients with advanced soft tissue sarcomas. Hypothesis: The addition of nivolumab will have synergistic effects and improve treatment outcomes. Methods: Primary objective: To assess progression-free survival; Secondary objectives: (1) To evaluate best overall response during treatment period confirmed in a 6-week follow-up, (2) PFS rate at 6 and 9 months, (3) Overall survival rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Inclusion criteria: Previously treated male and female subjects, > 18 years of age, pathologically confirmed diagnosis of locally advanced, unresectable, or metastatic sarcoma, measurable disease by RECIST v1.1, and acceptable hematologic and organ functions. Exclusion Criteria: History of autoimmune disorder. Treatment schedule: Metronomic doses of gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, and nivolumab (240 mg) on Day 1 only. Repeat treatment cycles may be given every three weeks if toxicity grade is <1. Results: This is an Interim Report on the modified Intent-to-treat population (n = 43). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. The most common histological subtypes in this group include leiomyosarcoma (n = 15), pleomorphic sarcoma (n = 4), synovial sarcoma (n = 4), liposarcoma (n = 3), osteosarcoma (n = 3) and other (n = 10). Best Overall Response = 2 CR (surgical CR), 6 PR, 30 SD, 5 PD. The disease control rate (CR+PR+SD) was 88.4%. Median PFS was > 4.6 (range: 1-27) months; 4 month PFS rate 60%. Median OS 6.2 months, with 4-month OS 74%. Historically, the median PFS on preceding lines of therapy was 2 (range: 1-14) months. There were no unexpected side effects noted in this study. The most common grade 3/4 TRAEs include Fatigue (n = 13), Nausea (n = 9), Neutropenia (n = 8), thrombocytopenia (n = 6), Anemia (n = 6). Conclusions: The GALLANT protocol using metronomic Gemcitabine, Doxorubicin (Adriamycin), Nivolumab, and Docetaxel (Taxotere) (1) is an effective regimen as second/third-line therapy for advanced sarcoma with no unexpected side effects, and (2) may have synergistic activity when this metronomic chemotherapy is combined with an immune checkpoint inhibitor. Clinical trial information: NCT04535713.

Correlation of TNF-α, IFN-γ and TGF-β Expression with In-vitro Fertilization Success Rates in Women with Recurrent Implantation Failure Undergoing Treatment with Intra-lipid Infusion

This study aimed at assessing the correlations between gene expression of TNF-α, IFN-γ, TGF-β in peripheral lymphocytes from women suffering from repeated implantation failure before and after intravenous Intra-lipid (IL) therapy, and correlation between changes in gene expression with IL infusion and success rate of IVF cycles. Twenty-three women complaining of unexplained infertility without history of autoimmune disorders, or immunodeficient diseases were included. All women included aged <40 years, BMI <28 with history of recurrent IVF cycles failure, seeking medical advice for new IVF trial. All were average responders to induction of ovulation (≥5 oocytes in each cycle) with good quality embryos transferred to uterus at proper time. Included women received 200 ml of 10% IL slowly intravenous. Two venous blood samples were taken from all candidates, one before IL infusion and the second was at day of embryo transfer. The current study detected a significant reduction of expression in TNF-α and increased expression of TGF-β, while non-significant reduction in expression of IFN-γ after treatment. Significant associations between reduction of TNF-α, IFN-γ expression and positive clinical and ongoing pregnancy were observed, while increased TGF-β expression was associated with only positive ongoing pregnancy. In conclusion, IL therapy might have a positive impact on IVF pregnancy rates via alterations in peripheral cytokines expression mainly reduction of TNF-α mRNA expression and increased TGF-β mRNA expression.

Helicobacter Pylori specific antibodies among multiple sclerosis patients

Background: Multiple sclerosis (MS) is one of the most common neurological diseases that occurs predominantly in young adults and more commonly in women. MS is a chronic inflammatory disease characterized by demyelinating lesions in the brain, spinal cord, and optic nerve. This study aimed to compare Helicobacter pylori infection in patients with MS and the control group.Methos: the study was case-control. And population consisted of patients referred to a neurological specialty clinic in Isfahan from 2015 to 2018, 107 cases in the case group and 107 in the control group. The case group was referred to causes such as headache, dizziness, and other diseases that had no established association with Helicobacter pylori. Case and control groups by referring to a laboratory through IgA and IgG antibodies against Helicobacter pylori were investigated.Results: The mean age in the case and control group was 32 years. The mean IgA in the case group was 17.03 and in the control group 29.25, which was statistically significant (p-value=0.001). The mean IgG in the case group was 26.53 and in the control group was 48.69 which statistically significant (P=0.001). After the adjustment of the IgA and IgG levels on the variables such as age, gender, smoking, and history of autoimmune disease, there was a significant difference between the two groups (P-value=0.001) and in the control group, the IgA level was 11.42 and IgG levels were 21.2 points higher than the control group.Conclusion: Generally. The results of this study showed that serum IgA and IgG antibodies in the control group were more than in the case group and there was a negative correlation between Helicobacter pylori infection and MS, and according to previous studies, the results of this study suggest that Helicobacter pylori infection has a protective role in the pathogenesis of MS.

Clinical presentation, outcome, and prognostic markers in patients with intravascular large B-cell lymphoma, a lymphoma study association (LYSA) retrospective study.

BackgroundIntravascular large B‐cell lymphoma (lVLBCL) is a very rare type of large B‐cell lymphoma.MethodsWe conducted a retrospective study on IVLBCL patients treated from 2000 to 2016 in LYSA cooperative group centers.ResultsSixty‐five patients were identified in 23 centers. Median age at diagnosis was 69 years (range 23–92). Thirty‐four patients (64%) had an IPI score >3 and 40 patients (67%) had a performance status ≥2. The most frequent extra‐nodal locations were bone marrow (n = 34; 52%), central nervous system (n = 25; 39%), and skin (n = 21; 33%). Nodal involvement and endocrine system were observed in 34% (n = 22) and 18% (n = 12) of all cases, respectively. Twenty‐six patients (41%) had macrophage activation syndrome. Tumor cells were frequently CD5 positive (52%) with a non‐germinal center origin (86%). BCL2 was expressed in 87% of all samples analyzed (n = 20) and 43% of patients had a MYC/BCL2 double expression. Fifty‐six patients were treated with a regimen of chemotherapy containing rituximab, among whom 73% reached complete remission. The median progression‐free survival (PFS) and median overall survival (OS) were 29.4 months and 63.8 months, respectively. History of autoimmune disorder (Hazard ratio [HR] 3.3 [1.4–7.8]; p < 0.01), nodal involvement (HR 2.6 [1.4–5.1]; p < 0.01), lack of anthracycline (HR 0.1 [0–0.4] for use; p < 0.001), or no intensification at first‐line regimen (p = 0.02) were associated with worse PFS. High‐dose methotrexate use was not associated with better PFS or OS.ConclusionsOur study highlights the aggressive clinical picture of IVLBCL, in particular the frequency of macrophage activation syndrome, and the need for new therapies despite a response to R‐CHOP‐like regimen similar to non‐intravascular diffuse large B‐cell lymphomas.

A past medical history of autoimmune disease predicts a future with fewer relapses in patients with ANCA-associated vasculitis

To explore the frequency and impact of an autoimmune disease past-medical history (PMH) in the clinical picture and outcomes of patients with antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV). This was a retrospective study of patients with biopsy-proven AAV, >16 years old, with detailed information about their PMH. Outcomes of interest included remission, treatment resistance, relapse, end-stage kidney disease (ESKD), and death. 206 patients with biopsy-proven AAV and available information regarding their PMH were studied. 63(30.6%) of them had a history of autoimmune disease prior to AAV diagnosis. The mean age overall was 54.1 years. One hundred and five patients (51%) were positive for PR3-ANCA, 101 (49%) for MPO-ANCA. Granulomatosis with polyangiitis was diagnosed in 79 (38.3%), microscopic polyangiitis in 97 (47.1%) and renal-limited vasculitis in 30 (14.6%) individuals. Remission rate was similar among patients with and without a PMH of autoimmune disease. Time-to-event analysis indicated that the relapse-free survival was significantly longer in patients with PMH of autoimmune disease (148.2 vs. 61.9 months, p-value <0.001). After adjusting for covariates, autoimmune disease history was associated with significantly lower risk of relapse (HR: 0.33, 95% CI: 0.15-0.72), which remained significant in males, patients ≥60 years old and those with C/PR3-ANCA, kidney and lung involvement. Patients with a PMH of autoimmune disease, prior to AAV diagnosis, experienced significantly fewer relapses after achievement of remission, compared to patients without such a history, underlining the importance of individualisation of maintenance immunosuppressive therapy, given the different aetiopathogenetic settings the disease was developed.

MO256: IGM in Fibrillary Glomerulopathy Linked to Monoclonal Gammopathy

Abstract BACKGROUND AND AIMS Fibrillary glomerulopathy (FGN) is a rare glomerular deposit disease accounting for less than 1% of annual native kidney biopsies. Its pathogenesis is still not fully understood. Immunofluorescence (IF) techniques in the vast majority of cases reveal the presence of smudgy polytypic IgG deposits associated with C3 and, anecdotally, of scarce IgM or IgA. The majority of cases are idiopathic, but up to one-third of patients may present with a secondary cause including monoclonal gammopathy, which in previously reported series ranged from 4% to 16% of the cases. The association of FGN and monoclonal gammopathy remains controversial, nonetheless monotypic cases in the absence of multiple myeloma, wäldestrom macroglobulinemia or high-grade lymphoma are currently included in the spectrum of monoclonal gammopathy of renal significance (MGRS). The aim of the study was to describe the role of IgM in FGN as a possible marker of an underlying MGRS. METHOD A single-center, retrospective and observational study of FGN cases diagnosed during the period of 2012–2019 was performed. Kidney biopsies were retrospectively reviewed. All cases had a confirmatory diagnosis made with electron microscopy (EM). Due to a lack of material and the novelty of the marker, DNAJB9 was not performed in all samples. IF on frozen tissue was done in all cases; digestion with proteinase K was done in cases of light chain restriction to unmask possible deposits. Demographics, clinical presentations, associated conditions and outcomes were reviewed. Data were expressed as mean standard deviation (SD). RESULTS Our cohort consisted of 17 patients, all but 2 caucasians, 9 males and 8 women, with a mean age of 63.1 ± 13.2. The mean follow-up was of 34.6 months. At the time of the diagnosis, most patients presented with hypertension 70% (12). All patients had proteinuria (mean 24-h protein excretion of 4.84 g ± 5.2) and renal impairment with a medium creatinine of 203.8 ± 202. Full nephrotic syndrome was present in 29% (5) of the cases and microhematuria in 52.9% (9); complement was normal in all cases. As for related medical conditions: 23% (4) had history of autoimmune diseases, 17% (3) had diagnosis of a solid tumor, 76.5% (13) were smokers (2 with diagnosed chronic obstructive pulmonary disease) and 29% (5) had diabetes mellitus. Monoclonal gammopathy was present in 35.3% (6/17) of the cases, all of which had an identified monoclonal component detected by electrophoresis with immunofixation (SPEPE/SIF). Three of them (50%) progressed (2 to multiple myeloma, 1 to amyloidosis AL) (Fig. 1). Light microscopic study showed three distinct patterns of glomerular injury, being mesangial pattern the most common 82% (14/17). Staining with congo red was negative in all cases, 17 cases. By immunofluorescence only 82% (13) showed glomerular positivity for IgG. Unexpectedly 23% (4) showed exclusively IgM deposits; three of them had monoclonal gammopathy. Looking in depth, 5/6 of the patients with monoclonal gammopathy showed IgM deposits in contrast to the non-associated FGN cases (3/10) (Fig. 2). No cases of GNF with IgM deposits had underlying cryoglobulinemia; there was one case of diabetes mellitus. A total of 41% (7) end up needing renal replacement therapy (RRT). No differences in the rate of RRT were observed between patients with monoclonal gammopathy and without. CONCLUSION IgM deposits were observed in patients with FGN cases associated with monoclonal gammopathy. IgM deposition is a finding rarely described in the literature up to the date. In this regard, we hypothesize that IgM monoclonal gammopathy due to a conformational alteration in the protein could generate deposits in the form of fibrils triggering a possible GNF. Thus, IgM deposition in the context of GNF could be a marker of a possible underlying MGRS. Future studies proving IgM conformational alterations in these patients could corroborate our hypothesis.

MO225: A Past Medical History of Autoimmune Disease Predicts a Future With Fewer Relapses in Patients With ANCA Vasculitis

Abstract BACKGROUND AND AIMS To explore the frequency and impact of an autoimmune disease past-medical history (PMH) in the clinical picture and outcomes of patients with ANCA-associated vasculitis (AAV). METHOD This is a retrospective study of patients with biopsy-proven AAV, &amp;gt;16 years old, with detailed information about their PMH. Outcomes of interest included remission, treatment resistance, relapse, end-stage kidney disease (ESKD), and death. RESULTS 215 patients with biopsy-proven AAV and available information regarding their PMH were studied. A total of 65 (30.2%) of them had a history of autoimmune disease prior to PIV diagnosis. The mean age overall was 53.9 years. One hundred and five patients (48.8%) were positive for PR3-ANCA, 101(47.2%) for MPO-ANCA, and 9(4.2%) were negative ANCA. Granulomatosis with polyangiitis was diagnosed in 79 (36.7%), microscopic polyangiitis in 101(47.0%) and renal-limited vasculitis in 35 (16.3%) individuals. Remission rate was similar among patients with and without a PMH of autoimmune disease. Time-to-event analysis indicated that the relapse-free survival was significantly longer in patients with PMH of autoimmune disease (148.2 versus 52.8 months, P-value &amp;lt; .001). After adjusting for covariates, autoimmune disease history was associated with significantly lower risk of relapse {HR 0.31, [95% confidence interval (CI) 0.14–0.69]}, which remained significant in males, patients ≥ 60 years old and those with C/PR3-ANCA, kidney and lung involvement. CONCLUSION Patients with a PMH of autoimmune disease, prior to AAV diagnosis, experienced significantly fewer relapses after achievement of remission, compared with patients without such a history, underlining the importance of individualization of maintenance immunosuppressive therapy, given the different etiopathogenetic settings the disease was developed.

Leveraging genetic correlation across immune-mediated disease to gain insights into underpowered studies of rare conditions

Abstract Prevalence of immune mediated disease (IMD) within N. European populations varies from common (atopic dermatitis AD=10%) to rarer (giant cell arteritis-GCA=0.02%; hidradenitis suppurativa-HS=0.77%). This directly affects statistical power to detect genomewide SNP associations and to identify “causal” genes. Objective Leverage genetic correlations between differently powered IMD cohorts to study the genetic mechanisms underlying multiple immune-mediated diseases. We used UK Biobank clinical data to create 18 IMD cohorts and a control set of individuals without any history of autoimmune disease (N=50,136). Using whole genome sequencing data from ~140K participants of the UKB, we performed SNP-level GWAS with REGENIE v2, and prioritized the associated genes using association statistics, in silico annotation, and eQTL information, as implemented in the Priority Index (Pi) algorithm. We used k-means clustering across relative gene rank distances optimized with the elbow method to group IMDs according to similar genetic architectures. Result IMD cohort size ranged from 196 to 3,411 cases and were each compared with a common set of controls. Optimal clustering yielded 4 groups, each with 6,5,4 or 3 IMD’s respectively. One cluster of interest contained HS, AD, vitiligo, GCA and Sjogren’s syndrome. This cluster reflects similarity in common “pathogenic” genes across IMD and highlights new candidate genes for further investigation that would otherwise go unnoticed in poorly powered studies of GCA and HS. In conclusion, our proposed use of genetic associations and clustering of their relative ranks across multiple disease phenotypes identified pathogenic genes in understudied IMDs that would otherwise not have been elucidated. Supported by Janssen Research &amp; Development

Acute Ischemic Stroke in a Young Woman with an Otherwise Asymptomatic SARS-CoV-2 Infection

It was well-observed that SARS-CoV-2 may cause a hypercoagulable state in hospitalized patients. Often these hospitalized patients exhibit severe upper respiratory symptoms with hypoxia, requiring high amounts of oxygen support. In this study, we report a young healthy 30-year-old woman with no medical problems, who experienced an embolic stroke due to an otherwise asymptomatic SARS-CoV-2 infection in July 2020. The patient presented to the emergency department after experiencing sudden slurred speech, dizziness, and acute left leg weakness during a social gathering on a river boat the day prior to admission. She also vomited once, non-bilious. The patient had no upper respiratory symptoms and had not been practicing social distancing nor wearing a mask. She did not have any sick contacts or significant travel history. Patient used oral contraceptives but never smoked. The workup included a Computed Tomography (CT) angiogram, an Magnetic Resonance Imaging (MRI) and an Magnetic Resonance Angiography (MRA) of the brain. It was significant for acute stroke with acute intraluminal thrombus causing partial occlusion of the distal basilar artery with left pontine stroke. Given that the onset of symptoms was greater than 4 hours, she was outside of the tissue Plasminogen Activator (tPA) administration window. Patient was also not a candidate for embolectomy as National Institute of Health Stroke Scale (NIHSS) was 3 and the occlusion was partial. SARS-CoV-2 PCR test was positive. D-Dimer level was elevated but CRP was normal. Echocardiogram was unremarkable. The patient had no history of autoimmune disorder. Patient was initially treated with antiplatelet medications aspirin and clopidogrel (Plavix). Her condition improved and she could ambulate with a front wheel walker and stand by to assist. She was discharged four days later with anticoagulation medication rivaroxaban (Xarelto) for 3 months. This case illustrates that patients with an otherwise asymptomatic SARS-CoV-2 infection may still suffer from complications of SARS-CoV-2. Do women on oral contraceptives have higher risk of arterial embolism when infected with SARS-CoV-2? More study is needed.

Turning walking pneumonia into recurrent abscesses: a curious case of CVID and review of the literature

BackgroundCommon variable immunodeficiency (CVID) is a primary immunodeficiency disorder associated with a broad symptom presentation that is still being characterized. We report a rare case of recurrent mycoplasma skin abscesses in a patient with a history of autoimmune disorders and prolonged mycoplasma pneumonia who was diagnosed with CVID.Case presentationA 34-year-old woman presented with a history of recurrent abscesses previously confirmed positive for Mycoplasma pneumoniae. Her past medical history of recurrent mycoplasma abscesses, prolonged mycoplasma pneumonia, and autoimmune disorders (mixed connective tissue disease and immune thrombocytopenia) raised suspicion of CVID. Workup included negative anti-mycoplasma antibody titers, hypogammaglobulinemia, and negative anti-pneumococcal antibody titers despite prior vaccination, solidifying the diagnosis of CVID. The patient was discharged on antibiotic and intravenous immunoglobulin therapy and now follows allergy and immunology long-term for treatment.ConclusionsHer diagnostic history underscores the importance of considering the various criteria of CVID for diagnosis, and her unique presentation of M. pneumoniae skin abscesses highlights the broad sequelae patients with CVID can manifest.

Management of primary hypothyroidism in adults: An analysis of the results of a survey in 546 primary care physicians

ObjectiveTo document current practices in the management of adult patients with hypothyroidism in the setting of primary healthcare. MethodsWe designed a web-based survey to inquire information on real-life practices regarding management of hypothyroidism by primary care physicians in the region of Madrid (Spain). ResultsIn total, 546 out of 3897 (14%) physicians (aged 50.9±8.5 yr, 404 females) completed the survey. More than 90% of respondents requested serum thyrotropin measurement in subjects with symptoms of thyroid hypofunction, family history of thyroid disease and history of autoimmune disease. A thyroid ultrasound was requested to evaluate subclinical and overt hypothyroidism by 27.1% and 69.6% of respondents, respectively. Only 22.1% of respondents stated that they do not treat subclinical hypothyroidism with thyrotropin values less than 10mU/l. Most physicians use brand-name formulations of levothyroxine and advise patients on how to take the tablets. To start treatment, the gradual replacement rate was the option chosen by most of the respondents, even in young patients. The thyrotropin target preferred by most respondents was 0.5–5.0mU/l, especially in older patients. In patients with persistent symptoms, 61.4% search for the causes through complementary investigations. A longer professional practice time was not always accompanied by better adherence to guidelines and expert recommendations. ConclusionOur results reveal a proactive attitude in the diagnosis and of therapy by most of the respondents. However, we observed a tendency to perform unnecessary diagnostic tests and an excessive propensity to treat mild subclinical hypothyroidism.

Relationships between Symptoms and Signs of Dry Eye Using Symptom Assessment in Dry Eye Questionnaires

Purpose: To investigate the pattern of Symptom Assessment in Dry Eye (SANDE) questionnaire symptom scores in dry eye disease (DED) patients and to assess the relationships with several dry eye signs.Methods: The medical records of 173 patients with DED were analyzed retrospectively. Each patient’s SANDE score and history of autoimmune disease and ocular surgery were investigated, and Schirmer’s test, tear film breakup time (TBUT), ocular surface staining score (OSS), tear osmolarity, and tear MMP-9 test were assessed. The distribution of SANDE scores and relationships between the SANDE score and various dry eye signs were analyzed. The relationships between the SANDE scores of TBUT (&lt; 5 / ≥ 5) and OSS (&lt; 3 / ≥ 3) subgroups were compared.Results: The average SANDE score was 52.6 ± 28.1. The SANDE scores were significantly higher in OSS ≥ 3 than in OSS &lt; 3 (79.1 ± 21.6 vs. 51.1 ± 27.6, p = 0.030), and TBUT ≥ 5 had marginally significantly lower SANDE scores than TBUT &lt; 5 (47.2 ± 25.6 vs. 55.6 ± 29.0, p = 0.050). TBUT was significantly negatively (R = -0.151, p = 0.024) correlated with the SANDE score, while OSS was marginally significantly positively (R = 0.111, p = 0.073) correlated. As OSS increased, the SANDE scores tended to increase (p for trend = 0.008). Other dry eye signs were not associated with the SANDE score.Conclusions: The DED symptom score from the SANDE questionnaire was related to TBUT and OSS, but there was still a discrepancy between the symptoms and signs of DED.

A59 A RARE PRESENTATION OF COLLAGENOUS GASTRODUODENITIS WITH 10 YEAR FOLLOW UP

Abstract Background Collagenous gastritis(CG) is a rare form of gastritis defined histologically by the presence of &amp;gt;10um of subepithelial surface collagen deposition. CG can further be categorized in childhood onset CG and adult onset CG. The prevalence of childhood CG is 2.1/100,000 in children aged younger than 18. Adult onset CG remains a rare entity. Here, we describe a rare presentation of collagenous gastroduodenitis in an adult patient and the interval progression over a 10 year period. Aims To increase awareness of a rare condition with limited data on available treatment modalities and clinical outcomes in adults. Methods Case Report Results A 35 year old female with no past medical history presented with worsening fatigue and increased shortness of breath with no overt gastrointestinal bleeding symptoms. There was no previous history of radiation exposure or family history of autoimmune disease. Laboratory investigations revealed iron deficiency anemia with a hemoglobin of 69 and a ferritin of 11. TTG serology and anti-parietal antibody was also negative. Esophagogastroduodenoscopy biopsies confirmed the diagnosis of collagenous gastritis localized to the gastric body with the presence of acute and chronic inflammatory changes. The patient was started on proton pump inhibitor therapy. In the interval period, the patient denies any new onset of gastrointestinal symptoms other than occasional heartburn. She remains iron deficient and requires regular iron infusions. Follow up endoscopy 10 years later now demonstrates diffuse mucosal abnormalities with a nodular contour involving the entire stomach and extending into the duodenal bulb. Biopsies showed features compatible with collagenous gastroduodenitis with active inflammation and pyloric metaplasia(Figure 1). There was atrophy of the stomach mucosa with no parietal cells identified and no endocrine hyperplasia. Immunostaining for Helicobacter pylori was negative. Flexible sigmoidoscopy was also performed revealing endoscopically normal colonic mucosa to the descending colon. Conclusions CG is a rare disease entity with unclear pathogenesis. Multiple case reports describe some association with autoimmune disease such as celiac disease. To date, no standard treatment has been identified for the management of CG. CG presents endoscopically with nodular changes, mucosal atrophy and collagen deposition. Over time, adult onset CG can progress to involve the entire stomach. Clinically, adult onset CG usually presents with a diarrhea predominant phenotype with associated collagenous colitis. Treatment modalities that have been trialed include PPI, corticosteroids, sucralfate, azathioprine,5-aminosalicylates, iron supplementation and hypoallergenic diets. Here we describe a rare presentation of collagenous gastroduodenitis and subsequent 10 year follow up in order to better understand this disease entity. Funding Agencies None

A phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.

291 Background: Combination systemic therapy with tyrosine kinase inhibitors (TKIs) and an immune checkpoint inhibitor (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We performed a phase I/II study to investigate the safety and efficacy combining the TKI axitinib (axi) with the IO agent nivolumab (nivo). Methods: This phase I/II study investigated the combination of axi and nivo in an initial dose finding phase I portion with a 3+3 design to determine the recommended phase 2 dose (RP2D) of axi. The phase II portion included 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs alone or IO/IO combination (NCT03172754). We are presenting results from the treatment naïve arm only. Included patients had to have histology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The RP2D of axi was 5 mg BID from the phase I portion and patients could be treated for up to 2 years. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Forty-four patients were accrued to the treatment naïve arm. One withdrew consent and was replaced but is included in the safety analysis, while 42 patients are evaluable for efficacy. The median age was 65 yrs (range: 42-84 yrs) and the group was predominantly male (83.7%) and white (95.3%). Using the IMDC risk group grading, 18 patients (41.9%) were favorable risk, 22 patients (51.2%) were intermediate risk and 3 patients (7 %) were poor risk. Median follow-up was 11.5 months. Best response data is shown in the table and is notable for an ORR of 69.0%, with only 1 patient (2.4%) experiencing primary progressive disease, for a disease control rate of 97.6%. Median progression free survival was 16.4 months (95% CI: 10.6 - 21.9 mo), and median overall survival (OS) was not reached. OS at 12 months was 86.7%. Adverse event (AE) data was similar to published data for IO/TKI combinations, with no grade 4-5 AEs. Twenty-nine patients experienced a grade 3 AE (70.7%), the most common of which was hypertension, and 14.0% discontinued the study due to treatment-related toxicity. Conclusions: The combination of axi/nivo for treatment naïve patients with mRCC demonstrated efficacy comparable to available IO/TKI combinations with a similar safety profile. Clinical trial information: NCT03172754. [Table: see text]

Abstract OT1-12-02: Trial in progress: Phase 2, open-label study to evaluate the safety and efficacy of praluzatamab ravtansine in metastatic HER2 non-amplified breast cancer as monotherapy and combination with pacmilimab

Abstract Background: Probody® therapeutic candidates (Pb-Tx) are masked antibodies designed to be conditionally activated in the tumor microenvironment by tumor-associated proteases. This allows Pb-Tx to address previously undruggable targets that are highly expressed in both tumor and normal tissues. Praluzatamab ravtansine is a masked antibody-drug conjugate targeting CD166 with a DM4 payload. A phase 1 monotherapy study showed safety and durable clinical activity (clinical benefit rate at 24 weeks [CBR24] 28%) in patients (pts) with metastatic HR-positive/HER2 non–amplified breast cancer (mHR+/HER2− BC) or metastatic triple-negative breast cancer (mTNBC). Pacmilimab, a masked PD-L1 inhibitor, demonstrated monotherapy activity in pts with TNBC with an acceptable tolerability profile.Trial design: This phase 2, open-label study with 3 parallel arms (~40 evaluable/arm) will evaluate praluzatamab ravtansine monotherapy (7 mg/kg Q3W) in pts with mHR+/HER2− BC or mTNBC, and praluzatamab ravtansine (7 mg/kg Q3W) combined with pacmilimab (1200 mg Q3W) in pts with mTNBC. Adult pts with an ECOG PS 0–1, measurable disease, and willingness to receive ocular prophylaxis for DM4-related toxicities will be enrolled. Key eligibility criteria for the mHR+/HER2− BC cohort include 2–4 prior regimens in the metastatic setting (excluding single-agent endocrine therapy). No CD166 screening required for HR+/HER2− BC but mTNBC must be CD166+. Pts with mTNBC must have received 1–3 prior metastatic regimens. For mTNBC pts who receive the doublet, key exclusion criteria include known PDL1 negative tumor, history of autoimmune disease, and progression within 120 days of 1st dose of an immuno-oncology agent. Pts with corneal disorders will be excluded. Primary endpoint is overall response rate (ORR) assessed by an independent radiology committee per RECIST v1.1. Secondary endpoints include ORR by investigator, duration of response, CBR16 &amp; 24, progression-free survival, and overall survival. This study will also evaluate safety and tolerability, pharmacokinetics, and antidrug antibodies with praluzatamab ravtansine as monotherapy and in combination with pacmilimab. This trial is enrolling (NCT04596150). Citation Format: Kathy Miller, Leisha A. Emens, Sara M. Tolaney, Sara A. Hurvitz, Erika Hamilton, Virginia Paton, Alison Hannah, Valentina Boni. Trial in progress: Phase 2, open-label study to evaluate the safety and efficacy of praluzatamab ravtansine in metastatic HER2 non-amplified breast cancer as monotherapy and combination with pacmilimab [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-02.

Neoadjuvant chemoradiotherapy with or without Pd-1 antibody sintilimab for pMMR/MSS/MSI-L locally advanced rectal cancer: A randomized controlled study (cohort B).

TPS210 Background: Neoadjuvant chemoradiotherapy (NACRT) could bring tumor downstaging and pathological response (pCR), and also survival benefit for locally advanced rectal cancer (LARC) patients. Several single arm prospective clinical trials have investigated combination effect of immunotherapy (PD-1 or PD-L1 antibody) and NACRT in LARC patients, such as the VOLTAGE clinical trial. A randomized trial is needed to confirm the benefit of immunotherapy in this setting and explore predictive biomarkers. This is a clinical trial with two cohorts according the MMR/MSI status (clinicalTrials.gov, NCT04304209). Methods: In this study, LARC patients with pMMR/MSS/MSI-L tumor will enter cohort B and be randomized into two arms. Main inclusion criteria include: cT3-4N0M0 or cTxN+M0 rectal adenocarcinoma, pMMR/MSS/MSI-L confirmed by immunohistochemistry or gene test, aged 18-75y; ECOG performance 0-1; no previous anti-tumor treatment for rectal adenocarcinoma. Main exclusion criteria include: active autoimmune diseases or a history of autoimmune diseases, and inadequate main organ functions. Patients in the experimental arm will receive four cycles of neoadjuvant PD1 antibody Sintilimab, Capeox chemotherapy and concurrent radiotherapy, followed by curative surgery or watch and wait, then four cycles of adjuvant Capeox chemotherapy. Patients in the control arm will receive four cycles of neoadjuvant Capeox chemotherapy and concurrent radiotherapy, followed by curative surgery or watch and wait, then four cycles of adjuvant Capeox chemotherapy Primary outcome measure is pCR rate. Secondary outcome measures include acute toxicity, tumor regression grade, R0 resection rate, local recurrence, distant metastasis. Sample size for this cohort is 134. Whole exome sequencing, RNA sequencing and immunohistochemistry of the rectal primary tumor are planned for biomarker searching and synergy effect mechanism investigation. The first patient has been enrolled in June, 2020. Clinical trial information: NCT04304209.

Cancer and Autoimmune Diseases: A Tale of Two Immunological Opposites?

The present article compares, side-by-side, cancer and autoimmune diseases in terms of innate and adaptive immune cells involvement, MHC Class I and Class II expression, TGFβ effect, immune modulating drugs effect and the effect of reactive oxygen species. The change in the inflammatory immune reaction during the progress of cancer and the effect of this change on the comorbidity of autoimmune diseases and cancer are discussed. The similar inflammatory properties of autoimmune diseases and early cancer, and the contrasting inflammatory properties of autoimmune diseases and advanced cancer elucidate the increased incidence of many types of cancer in patients with pre-existing autoimmune diseases and the decreased cancer-specific mortality of these patients. Stage-dependent effects of reactive oxygen-species on tumor proliferation are an additional probable cause for these epidemiological observations. The relationship: {standardized incidence ratio (SIR)} > {cancer-specific hazard ratio (HR)} for cancer patients with a history of autoimmune diseases is substantiated and rationalized.

Association Between Autoimmune Diseases and Spontaneous Cervicocranial Arterial Dissection.

A series of biopsies and reports showed autoimmune diseases might be involved in the process of local inflammation related to spontaneous cervicocranial arterial dissection (SCCAD) occurrence. This retrospective case-control study examined the association between SCCADs and autoimmune diseases in patients and control subjects from 2014 to 2020. SCCAD patients and age/sex-matched control subjects were recruited, and clinical data were collected. SCCAD was confirmed by digital subtraction angiography or high-resolution magnetic resonance imaging. The study included 215 SCCAD patients and 430 control subjects. Totally, 135 (62.8%) of the 215 cases were found SCCAD in the anterior circulation, 26 (12.0%) patients involved multiple vessels. Autoimmune disease occurred in 27 (12.6%) cases with SCCAD and 4 (0.9%) control subjects (p<0.001). A conditional multivariable logistic regression model was used to calculate the odds ratio for SCCAD among patients with a history of autoimmune disease, adjusting for hypertension, diabetes, hyperlipidemia, and smoking. After adjustment, autoimmune diseases were associated with SCCAD (p<0.001). After sub-analysis by a similar modeling strategy, significant associations were still observed in different subgroups, such as female group and male group as well as intramural hematoma (IMH) group and Non-IHM group. The association of SCCAD with autoimmune disease suggested that autoimmune mechanisms may be involved in some etiologies of SCCAD.

Immune Dysregulation in Patients With Chromosome 18q Deletions-Searching for Putative Loci for Autoimmunity and Immunodeficiency.

IntroductionAutoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions.Material and MethodsMedical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG1-4 serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR—a free web resource for gene prioritization.Results18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min–max: 4.0–33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG1-4) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls.ConclusionsPatients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21.