Elevated IgG4 Levels Research Articles

POS0782 FOLLICULAR DENDRITIC CELL NETWORKS IN MINOR SALIVARY GLAND BIOPSIES: A MARKER OF DISEASE ACTIVITY AT BASELINE AND DURING THE FOLLOW-UP IN SJÖGREN’S SYNDROME

Background:Minor salivary gland biopsy (MSGB) has been increasingly recognized as an important tool for the stratification of patients with primary Sjögren’s syndrome (pSS). Recently, the presence of follicular dendritic cell (FDC) networks in the inflammatory infiltrate has been associated with more severe biological and serological abnormalities compared with less organized infiltrates.Objectives:To investigate the associations between the presence and number of FDC networks in foci and pSS glandular and extra-glandular disease activity at baseline and during the follow-up.Methods:Consecutive MSGBs performed in daily practice for clinically suspected pSS from January 2017 to October 2020 were reviewed. Patients’ demographic, clinical, biological and serological data were obtained from medical records. The ESSDAI was used to measure disease activity at baseline and at the end of the follow-up in pSS patients. For histopathology, 3 µm sections were cut from each formalin-fixed paraffin-embedded block of MSGBs and stained with haematoxylin and eosin (H&E). Immunohistochemical stainings were performed on additional 3 μm sections in order to detect T lymphocytes (CD3), B lymphocytes (CD20) and follicular dendritic cells (CD21). Glandular tissue areas, number of foci, focus score (FS) and the presence and number of FDC networks were assessed.Results:We reviewed 330 consecutive MSGBs from patients with suspected pSS: out of them 146/330 (44%) were classified as nonspecific chronic sialadenitis (NSCS) whereas 184/330 (56%) as focal lymphocytic sialadenitis (FLS). According to the ACR/EULAR criteria the diagnosis of pSS was confirmed in 130 patients (117 F:13 M, age 56±13 yrs). The mean (S.D) surface area of the MSGBs was 7.8 (3.9) mm2. The number of foci in the FLS samples ranged from 1 to 12 (mean (S.D)=3.1 (2.6)), whereas the FS ranged from 0.3 to 9.0 (mean (S.D) = 1.4 (1.2)).The presence of FDC networks was documented in 106/330 (32%) of the samples; in 54/106 (51%) of these MSGBs the number of FDC networks ranged from 2 to 8 (mean (S.D)=3.1 (1.4)). The number of FDC networks significantly correlated with the number of foci (r=0.721**) and FS (r=0.707**). Patients with FDC networks in the inflammatory infiltrate presented more serological abnormalities (i.e anti-Ro/SSA, anti-LA/SSB, Rheumatoid factor) and elevated IgG levels (p<0.001). In pSS patients, the number of FDC networks slightly correlated also with C4 levels (r=-0.216*), peripheral lymphocyte count (r=-0.274**) and with glandular (r=0.213*), and biological (r=0.230**) domains of the ESSDAI at baseline. After a mean (S.D) follow-up of 21(13) months, the number of FDC networks still correlated with the final total ESSDAI (r=0.312**).Conclusion:The presence and number of FDC networks in foci represent a useful histopathological parameter able to reflect disease activity at baseline and during the follow-up, thus allowing more personalized interventions.Disclosure of Interests:None declared

Prednisone-Responsive Hypercalcemia in a Patient With IgG4 Disease and Elevated Serum PTHrP Levels

Background: Ninety percent of hypercalcemia cases are related to either primary hyperparathyroidism or malignancy (1). This case presents one of the atypical etiologies of hypercalcemia. Clinical Case: A 53-year-old man with past medical history of nephrectomy was admitted for acute respiratory distress syndrome secondary to SARS-CoV-2. Hospital stay was complicated by septic shock and acute kidney injury requiring hemodialysis. Three months post hospital admission, the patient developed non-parathyroid (PTH) mediated hypercalcemia. Lab work results showed elevated serum calcium of 12.7 mg/dl (8.6–10.6), ionized calcium 6.8 mg/dl (4.2–5.4), albumin 2.6 g/dl (3.4–5.4), serum creatinine of 3.5 mg/dl (0.5–1.5), eGFR of 18.4 ml/min, and a PTH of 4 pg/ml (12–88). Liver profile - total bilirubin of 10.5 mg/dl (0–1.2), direct bilirubin of 5.9 mg/dl (0–0.2), GGTP 2055 U/L (6–60), alkaline phosphatase of 936 u/L (40–125), bone fractionated alkaline phosphatase 216 u/L (0–55), 25-OH Vitamin D of 11 ng/nl (20–80), 1,25 OH vitamin D of <5 pg/ml (19–79), TSH of 3.56 mciu/mL (0.35–4.0), CPK of 20 u/L (21–232) and a normal SPEP and immune-electrophoresisTreatment for hypercalcemia was initiated with calcitonin and oral steroids (prednisone 40mg/day for 4 days, 20mg/day for 1 day, and 10mg/day for 2 days), resulting in normalization of serum calcium. Patient received tube feedings that contained 2192 mcg retinol activity equivalents of vitamin A daily, which is associated with vitamin A intoxication in the presence of renal insufficiency. Vitamin A returned 0.78 mg/L (0.3–1.2). Serum Parathyroid hormone-related peptide (PTHrP) was elevated at 12.4 pmol/L (0.0–2.0). There was no obvious malignancy on various imaging studies. A magnetic resonance cholangiopancreatography (MRCP) showed biliary stricturing suggestive of primary sclerosing cholangitis (PSC), however, liver biopsy was not consistent with PSC. Serum IgG4 level was found to be elevated to 142 mg/dl (range: 1–123) which raised suspicion for autoimmune cholangiopathy. Discussion: Patient presented with non-PTH mediated hypercalcemia with low serum 1,25 OHD levels and elevated serum PTHrP level. Although most cases of elevated PTHrP associated with hypercalcemia are due to solid tumors, increased PTHrP levels have been seen in hypercalcemic patients with hematological malignancies and rare benign causes such as pneumonia (5). Association of elevated hypercalcemia with elevated IgG4 levels and PTHrP levels has not been previously reported. MRCP findings and abnormal morphology detailed in liver biopsy are suggestive of IgG4-related disease (IgG4RD) (3). The responsiveness in hypercalcemia to prednisone also supports this diagnosis. IgG4RD is associated with multi-organ autoimmune involvement. This case report highlights another complication of IgG4RD (i.e. hypercalcemia) associated with elevated PTHrP levels.

Republican registry of primary immune deficiencies in the chuvash republic and description of postvaccinal immunity disorders in a pregnant patient with common variable immune deficiency

In recent years, primary immunodeficiencies have turned from the class of rare diseases to the category of more common disorders which may be encountered by doctors of any clinical discipline. The first case of primary immunodeficiency disorder (PID) in Chuvashia was detected in 1993. Since that time, the Department of Internal Diseases with the Course of Clinical Immunology at the I. Ulyanov Chuvash State University registered all the cases of PID diagnosed in the region, introducing them into the Republican Registry of PID. The study was aimed for searching epidemiological indexes, clinical and laboratory manifestations of PID in Chuvash region. The study was based on the patient data obtained by retrospective analysis of 85 case histories of PID patients, treated at different departments of the Republican Clinical Hospital, and the City Chuvash Pediatric Clinical Hospital of Public Health Ministry in 2000-2019, as well as on 49 outpatient records of the patients included into the Regional PID Registry. Various forms of PIDs were diagnosed according to the criteria developed by the European Society for Immunodeficiency and the Pan-American Group on Immunodeficiency (1999). The results of this study showed that the incidence of PID in the Chuivash Region is 3.4:100,000. The incidence of common variable immune deficiency (CVID), the most common form of PID in the region, was 1.58 per 100,000 population. The average age at the time of CVID diagnosis in Chuvash patients was 30.4±16.1 years, and the age of CVID debut was 11.3±15.0 years. The delay in proper diagnosis from the moment of clinical manifestation of CVID was, on average, 17.9 years in the region. At the time of CVID diagnosis, the patients showed marked decrease in the levels of 3 or 2 immunoglobulin classes (IgG and IgA), and T-helper cell contents (CD3+CD4+) in peripheral blood. Prevalence of selective IgA deficiency with сlinical symptoms was 0.83 per 100,000 population of the region, and the incidence of the asymptomatic form of this PID was 1 : 167. In patients with selective IgA deficiency, there were also disorders in the T cell system manifesting as decreased relative number of cytotoxic T-cells as well as elevated IgG and IgM levels. The age of diagnosis of X-linked agammaglobulinemia in the region was 3.5±3.0 years. In addition to disturbances of humoral adaptive immunity in children with this disease, a decrease in absolute T cell numbers was detected. In conclusion, the article describes disturbances of postvaccinal immunity in a pregnant patient with CVID, with asymptomatic clinical course, thus leading to false interpretation of the serological markers of TORCH infections and wrong strategy of pregnancy management.

Plasmodium falciparum VAR2CSA-Specific IgG Subclass Responses Reflect Protection Against Low Birth Weight and Pregnancy-Associated Malaria.

Sequestration of Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen in the placenta results in poor pregnancy outcomes, including low birth weight and maternal anemia. Antigen-specific antibody-mediated immunity is acquired during successive pregnancies. Thus, evaluating VAR2CSA-specific IgG profiles among pregnant women will increase knowledge on the immunological mechanisms associated with protection, and help in the development of VAR2CSA-based placental malaria vaccines. Using the PAMVAC candidate vaccine antigen, we assessed anti-VAR2CSA IgG subclass responses of a cohort of pregnant Beninese, and analyzed their relationships with pregnancy outcomes. Cytophilic IgG1 and IgG3 responses were the most frequent, with prevalences ranging from 28% (IgG3) up to 50% (IgG1). Elevated levels of VAR2CSA-specific total IgG and cytophilic IgG3 during pregnancy were consistently associated with higher birth weights, whilst high levels of IgG4 were associated with a reduced risk of placental infections. This suggests that protective anti-VAR2CSA IgG responses are coordinated between both cytophilic and non-cytophilic antibodies.

Immunization with Brugia malayi Calreticulin Protein Generates Robust Antiparasitic Immunity and Offers Protection during Experimental Lymphatic Filariasis.

Lymphatic filariasis causes permanent and long-term disability worldwide. Lack of potent adulticidal drugs, the emergence of drug resistance, and the nonavailability of effective vaccines are the major drawbacks toward LF elimination. However, immunomodulatory proteins present in the parasite secretome are capable of providing good protection against LF and thus offer hope in designing new vaccines against LF. Here, we evaluated the immunogenicity and protective efficacy of B. malayi calreticulin protein (BmCRT) using in vitro and in vivo approaches. Stimulation with recombinant BmCRT (rBmCRT) significantly upregulated Th1 cytokine production in mouse splenocytes, mesenteric lymph nodes (mLNs), and splenic and peritoneal macrophages (PMΦs). Heightened NO release, ROS generation, increased lymphocyte proliferation, and increased antigen uptake were also observed after rBmCRT exposure. Mice immunized with rBmCRT responded with increased Th1 and Th2 cytokine secretion and exhibited highly elevated titers of anti-BmCRT specific IgG at day 14 and day 28 postimmunization while splenocytes and mLNs from immunized mice showed a robust recall response on restimulation with rBmCRT. Infective larvae (L3) challenge and protection studies undertaken in Mastomys coucha, a permissive model for LF, showed that rBmCRT-immunized animals mounted a robust humoral immune response as evident by elevated levels of total IgG, IgG1, IgG2a, IgG2b, and IgG3 in their serum even 150 days after L3 challenge, which led to significantly reduced microfilariae and worm burden in infected animals. BmCRT is highly immunogenic and generates robust antiparasitic immunity in immunized animals and should therefore be explored further as a putative vaccine candidate against LF.

Eosinophilic Esophagitis and IgG4: Is There a Relationship?

Our knowledge of the pathophysiology of eosinophilic esophagitis is constantly evolving. There is significant association between eosinophilic esophagitis and atopy; however, multiple studies have refuted the role of IgE in its pathogenesis. Instead, new data have demonstrated an elevated IgG4 level in patients with eosinophilic esophagitis. We review the current understanding of eosinophilic esophagitis pathogenesis and highlight the increasing evidence for the role of IgG4.

Adjuvant activities of crude polysaccharides from cultivated Artemisia rupestris L. on TH1-biased response with the induction of DC activation

ABSTRACTArtemisia rupestris L. polysaccharides have immune enhancement effects with low toxicity in the previous studies. The effect of crude polysaccharides from cultivated Artemisia rupestris L. (CPCAR) on immunity has not been explored. Here, the adjuvant potential of CPCAR was investigated in vivo and its underlying mechanism in vitro was explored through activation of bone marrow-derived dendritic cells (BMDCs). After intramuscular immunizations, CPCAR elevated IgG levels with a TH1-biased response, lymphocyte proliferation and increased CD4 and CD8 T cells in spleen and lymph nodes. IFN-γ and IL-4 of CD8 or CD4 T cells were specifically increased. CPCAR improved DC maturation and diminished Treg frequency. BMDCs treated with CPCAR in vitro showed the up-regulation of CD40, CD86, IL-12 and TNF-α. BMDMs pretreated with TLR4 and NF-kB inhibitors decreased the expressions of CD40 and CD86 and produced less cytokines. These data demonstrated that CPCAR could boost TH1-biased response through DC activation in TLR4/NF-κB signalling.

Infektivna mononukleoza i autoimuni hepatitis

Introduction: The case report shows a sick nine-year-old girl whose disease initially manifested as infectious mononucleosis. Encountering infectious mononucleosis in pediatrics is quite common and it is estimated that as much as 50% of children are infected with the Epstein-Barr virus before the age of 5. Suspicion of mononucleosis emerges every time there is a patient with swollen neck lymph nodes, fever, painful and difficult swallowing. However, the laboratory findings in the second month of the onset of the disease raised suspicion for autoimmune disease. Case report: Based on the clinical manifestations, the patient underwent a series of examinations such as biochemical analyses, blood count, and Epstein-Barr virus serology, as well as abdominal ultrasound and testing of ceruloplasmin and Alpha-1 antitrypsin values. The autoimmune disorder was confirmed after detecting elevated IgG levels, the presence of anti-LKM antibodies, and interface hepatitis as a pathoanatomic substrate of liver bioptates. Conclusion: The case report presents the Epstein-Barr virus as a direct trigger of autoimmune hepatitis. This DNA virus known for its cytopathic effect on B lymphocytes induced the swelling of lymph nodes, liver, and spleen. Its overall impact on B lymphocytes and the liver led to producing specific autoantibodies and infiltrating hepatic nodes with lymphocytes.

Worse Response to Ursodeoxycholic Acid in Primary Biliary Cholangitis Patients with Autoimmune Hepatitis Features

Background: There is limited evidence on the treatment response of primary biliary cholangitis (PBC) with autoimmune hepatitis (AIH) features but not meet the criteria of PBC-AIH syndromes. The aim of this study was to elucidate the clinical characteristics of PBC patients with features of AIH. Methods: We included patients with diagnostic criteria of PBC. All patients were treated with ursodeoxycholic acid (UDCA) and without immunosuppressive agents for >1 year. The biochemical response was evaluated at 1 year after the treatment of UDCA. Results: Among 432 patients with PBC, 166 (38.4%) patients did not achieve biochemical response within 1 year of UDCA treatment. Nonresponders had a lower albumin level and higher immunoglobulin G, alanine transaminase (ALT), alanine aminotransferase (AST), alkaline phosphatase, glutamyl transpeptidase and total bilirubin levels (p < 0.05). The response rates were significantly lower in patients with elevated level of IgG or ALT or AST. Moreover, the higher the IgG or AST level was, the lower the response rate was in patients with PBC, regardless of cirrhosis. For patients with cirrhosis, there was no differences among patients with different levels of ALT. Patients in the PBC with AIH features group had a significant lower response rate than patients in the PBC-only group. Among the 139 patients who underwent liver biopsy, 54 were nonresponsive to UDCA and 48 (88.9%) shown mild interface hepatitis. Conclusion: In conclusion, PBC patients with AIH features had a worse response to UDCA therapy.

Abstract 16811: In-Utero Coxsackievirus Type B Infection is Associated With Congenital Pulmonary Atresia

Introduction: Maternal exposure to various pathogens during pregnancy has been well established as a cause of congenital heart defects (CHD). Suggestive, although inconclusive, data exists of an association between Coxsackievirus B (CVB) infection during pregnancy and CHD. Therefore, this study was undertaken to examine association between perinatal infection with CVB and CHD. Hypothesis: CVB infection during pregnancy may play a role in the pathogenesis of CHD. Methods: In a prospective study of 122 pregnant women with pregnancies affected with CHD, circulating CVB IgG and IgM antibodies in the maternal serum were quantified. To determine specific CVB serotypes involved, Neutralizing antibodies (NA) were measured against three CVB serotypes: CVB1-Chi07, CVB3, Nancy, and CVB4, J.V.B. Results: A significant number of the women were positive for CVB antibodies; 31.1% for IgG and 6.6% for IgM. Elevated levels of IgG were seen in 50% of women carrying babies with Pulmonary Atresia (PA) (p=0.04). In addition, 55.6% (p=0.100) of moms carrying babies with Hypoplastic Left Heart Syndrome (HLHS), aortic atresia/mitral stenosis (AA/MS) variant and 47.1% (p=0.127) of HLHS AA/mitral atresia (MA) had positive IgG levels. Among babies of women with positive IgM titers, 75% (p=0.001) had isolated Ventricular Septal Defect (VSD), comprising 26.1% (6/23) of all babies with isolated VSD in the cohort.We also show a possible association between CVB4 and CHD in the cohort. All mothers with positive IgM titers whose babies were born with a VSD had elevated CVB4 NA (p=0.001). Among women with elevated IgG having babies with PA, 40.0% (p=0.061) had elevated CVB1 NA, 70.0% (p=0.014) had elevated CVB3 NA, and 40.0% (p=0.876) had elevated CVB4 NA. Conclusion: We present data from a clinical study suggesting that CVB infection during pregnancy may contribute to the burden of CHD in affected babies. Our data demonstrates not only an association of CVB with CHD in pregnant women but this is the first report showing significant association between in-utero CVB infection and PA. Our study has broad implications for the future understanding and potential management of CHD as well as introduces a new avenue of research for cardiac defects.

B cell-specific GPR55 deficiency promotes atherosclerosis

Abstract Background Atherosclerosis is accompanied by an imbalance between resolving and pro-inflammatory lipid mediators. Targeting lipid signaling pathways might offer a new anti-inflammatory therapy for improving the clinical outcome in cardiovascular disease patients. We considered lysophosphatidylinositol (LPI) and its receptor G protein-coupled receptor (GPR)55 as a potential modulator of atherosclerosis. Its role in regulating atherosclerosis and B cell function is unknown. Hypothesis We assessed the hypothesis that GPR55 signaling causally affects atherosclerosis and whether it has a specific role in regulating B cell function in this disease. Methods Atherosclerotic plaques were compared between apolipoprotein E deficient (ApoE−/−) and ApoE−/−Gpr55−/− mice after 4 to 16 weeks Western Diet (WD; 0.15% cholesterol; n=12–15 per group). To specifically test the role of B cell GPR55 in atherosclerosis, we generated mixed chimeras by lethally irradiating low density lipoprotein receptor deficient (Ldlr−/−) mice and reconstituting with a mixture of μMT and wildtype (control) or μMT and Gpr55−/− bone marrow cells. Circulating B cells were sorted and bulk RNA sequencing analysis was performed. We performed lipid and immunostainings of murine aortic root plaques, qPCR and ELISA of tissue lysates, as well as multiplex analysis of plasma immunoglobulins. Leukocyte plasma and tissue counts were determined by flow cytometry. Results GPR55 expression in mouse and human atherosclerotic plaques was detected by immunostaining. Furthermore, we confirmed murine Gpr55 mRNA expression on sorted circulating B220+B cells via qPCR, which was higher compared to CD3+ T cells, while CD11+ myeloid cells as well as NK cells had only low Gpr55 mRNA levels. ApoE−/−Gpr55−/− mice had significantly larger plaques after 4&amp;16 weeks WD compared to ApoE−/− controls, with more pronounced body weight increases and higher cholesterol levels at the 16 weeks WD time point. In addition, global Gpr55 deficiency resulted in enhanced aortic pro-inflammatory cytokine mRNA expression (IL-1β, IL-6, TNFα) and a massively upregulated IgG1 plasma levels and increased percentages of splenic germinal center and plasma cells. B-cell RNA-seq analysis showed 460 differential expressed regulated genes in the ApoE−/−Gpr55−/− compared to ApoE−/−. The main pathways affected were calcium ion transport, immunoglobulin production, negative regulation of phosphorylation, and cellular component morphogenesis, suggesting a dsysregulation of B cell function. B cell specific Gpr55 deficiency blunted the metabolic effects on body weight and cholesterol, but still translated in larger atherosclerotic plaques and elevated plasma IgG levels compared to the respective controls. Conclusion Both global and B cell-restricted Gpr55 deficiency promotes atherosclerosis and is associated with a more pro-inflammatory phenotype. Our findings suggest a novel role for GPR55 in regulating B cell development and function. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Hypocomplementemic cutaneous small vessel vasculitis in a patient with IgG4-related disease

A 62-year-old man was diagnosed with IgG4-related disease based on multiple sites of lymphadenopathy, lymph node biopsy, and elevated serum levels of IgG4. Hypocomplementemia was also observed. During admission, he was referred to our department complaining of multiple areas of purpura on the lower legs. Histological examination revealed leukocytoclastic vasculitis with fibrinoid necrosis, neutrophil infiltration, and nuclear dust in the upper dermis. To date, only a few cases of cutaneous vasculitis have been reported in IgG4-related disease, all of which showed hypocomplementemia. The role of IgG4 in the etiology of leukocytoclastic vasculitis in IgG4-related disease remains unknown and further studies are necessary.

Immunoglobulin-G4–related skin disease

Immunoglobulin-G4–related disease (IgG4-RD) is an autoimmune-mediated spectrum of diseases, characterized by infiltration of IgG4+ plasma cells into one or multiple organs, with the pancreas being the most commonly affected organ. The disease mostly affects middle-aged to elderly men. Diagnosis requires an integration of clinical, radiologic, pathologic, and serologic studies. Histologically, there is an increased infiltration of IgG4+ plasma cells, elevated ratio of IgG4+/IgG plasma cells of more than 40%, and a storiform pattern of fibrosis. There may be eosinophilia, along with elevated IgG4 levels. IgG4-RD can mimic several diseases and should be differentiated from inflammatory and neoplastic processes. Recently, there has been increased awareness of cutaneous involvement by IgG4-RD either as an isolated lesion or primary involvement or as a secondary involvement from a systemic disease. Clinically, cutaneous IgG4+-related disease presents as papules, plaques, and nodules involving the head and neck areas. We have provided a systematic review of the literature of this new and challenging entity of cutaneous IgG4-RD.

Anti-Neutrophil Extracellular Trap Antibodies and Impaired Neutrophil Extracellular Trap Degradation in Antiphospholipid Syndrome.

The release of neutrophil extracellular traps (NETs) by hyperactive neutrophils has recently been recognized to play an important role in antiphospholipid syndrome (APS). This study was undertaken to evaluate autoantibodies targeting NETs in patients with primary APS, and to determine their potential functions and clinical associations. We measured global anti-NET activity in 76 patients with primary APS, 23 patients with systemic lupus erythematosus without antiphospholipid antibodies (aPL), 11 patients with a history of unprovoked venous thrombosis without aPL, and 44 healthy controls. The ability of APS sera to degrade NETs was also assessed. We found markedly elevated levels of anti-NET IgG and IgM in patients with primary APS compared with healthy controls (for IgG, mean ± SD optical density 0.55 ± 0.34 versus 0.33 ± 0.17; for IgM, mean ± SD optical density 0.76 ± 0.51 versus 0.26 ± 0.23). This anti-NET activity did not correlate with levels of traditional aPL and was relatively stable over time. Mechanistically, anti-NET antibodies (especially of the IgG isotype) impaired the ability of patient sera to degrade NETs (r = 0.4, P = 0.003). Levels of anti-NET IgM inversely correlated with complement C4 (r = 0.4, P = 0.019). Clinically, anti-NET antibodies associated with certain APS clinical manifestations, and in particular recurrent venous thrombosis (odds ratio 4.3; P = 0.002). Interestingly, anti-NET antibody levels also appeared to be associated with unprovoked venous thrombosis in the general population (for IgM, mean ± SD optical density 0.67 ± 0.34 versus 0.26 ± 0.23). Our data indicate high levels of anti-NET antibodies in patients with primary APS, which may impair NET clearance and activate the complement cascade. These findings may ultimately enable more effective risk stratification.

S1579 Diagnosis of Autoimmune Pancreatitis via Fine Needle Biopsy and HISORt Criteria in a 43-Year-Old African American Male With an Atypical Presentation

INTRODUCTION: Autoimmune pancreatitis (AIP) is a rare disorder characterized by abnormal imaging, elevated IgG4 levels in a majority of cases, typical histology, and usually a perceptible response to steroids. It is further divided into two different subsets, Type 1 and Type 2, with different characteristics and histology. It is difficult to diagnose this condition via a fine needle aspiration (FNA) sample due to scant tissue retrieval; hence other diagnostic criteria like HISORt, as proposed by the Mayo Clinic, are often used. It utilizes histology, imaging, serology, other organ involvement, and response to steroid therapy. CASE DESCRIPTION/METHODS: We report an atypical presentation of autoimmune pancreatitis in a 43-year-old African American male who presented with abdominal pain, diarrhea, a 40 lb weight loss, pancreatic mass, and no known history of autoimmune diseases. Comorbidities include hypertension and diabetes mellitus. An EUS with Fine Needle Biopsy (FNB) was performed, which demonstrated an adequate sample with classic lymphoplasmacytic reaction, which stained positively for IgG4. Serum IgG4 levels were also elevated. A diagnosis of Type 1 AIP was made. The patient’s fecal elastase was low, denoting Exocrine Pancreatic Insufficiency (EPI). He was started on a prednisone taper, along with azathioprine 50 mg and weight-based Creon therapy. Six months post intervention, the patient is symptom free and has regained 15 lbs. DISCUSSION: This case demonstrates the value of the FNB sampling technique to obtain accurate and adequate tissue histology that is not only diagnostic but can further differentiate between Type 1 and 2 AIP, along with validation of the HISORt criteria. In addition, it demonstrates the value of screening for EPI in patients with AIP.Figure 1.: Diffusely thickened appearance of the pancreas and an ill-defined, bi-lobed cystic area at the tail, measuring 1 × 2cm, contiguous with the lower pole of the spleen. Mild splenomegaly and interval development of a slightly irregular cystic splenic mass, measuring 4.5 × 4.3cm.Figure 2.: A 4.8 × 4.1cm oval and hypoechoic lesion at the junction of the body and tail of the pancreas. Calcified mass with a cystic and necrotic component, concerning for a pseudocyst.Figure 3.: A: IgG4 staining, B: MUM-1 staining, C: Storiform fibrosis with lymphoplasmacytic infiltrate, D: Atrophic pancreatic acinar epithelium with fibrosis and inflammation.

S1436 Outcome of the Use of Corticosteroids for Treatment of Autoimmune Pancreatitis (AIP) in a COVID-19 Patient

INTRODUCTION: Autoimmune Pancreatitis (AIP) is a steroid-responsive disease of the pancreas. Due to poor outcomes in severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV) outbreaks, the World Health Organization (WHO) advises against the use of corticosteroids in the treatment of 2019 Coronavirus Disease (COVID-19) except if steroid therapy is required for coexisting illness. We present a case of uncontrolled AIP which was treated with high dose steroids while the patient was hospitalized with COVID-19. CASE DESCRIPTION/METHODS: A 53-year-old male was hospitalized with COVID-19 and uncontrolled AIP. The patient had elevated IgG4 levels and negative work up for other etiology of pancreatitis in the past and was already taking prednisone 40 mg daily due to a recent AIP exacerbation. On physical exam, temperature of 101 F, heart rate 101 beats/minute, respiratory rate 20 breaths/minute while blood pressure was normal. Tenderness in the epigastric region was noted. Labs showed Hct 35.8%, WBC 12.32 thousand/uL, BUN 9 mg/dL, lipase 530 u/L and normal LFTs. CT abdomen showed severe necrotizing pancreatitis with infected necrosis (multiloculated collections of gas and fluid) (Image 1). Chest imaging showed bibasilar infiltrates consistent with COVID-19 pneumonia (Image 2). Patient was continued on steroids, started on meropenem, and supportive treatment for COVID-19. Due to persistent abdominal pain and inability to tolerate oral intake, the patient underwent CT-guided percutaneous drainage of the necrotic collection. Azathioprine (AZA) was added to treatment regimen due to uncontrolled AIP despite steroid therapy. Patient recovered clinically without need for oxygen supplementation or further complication from COVID-19. He was discharged from the hospital with a short antibiotic course, a prescription to continue AZA and prednisone 40 mg with plan to taper dose by 5 mg per week. He returned home to continue quarantine which he completed without problems. DISCUSSION: Despite having multiple risk factors associated with poor outcomes in COVID-19 (age greater than 45 years, male gender, comorbidity due to uncontrolled AIP and immunosupression with steroid treatment), our patient experienced complete resolution of the illness with supportive measures. Our case supports current recommendations advocating steroid therapy for co-existing diseases in patients with COVID-19.Figure 1.: Image 1. CT scan abdomen shows multiloculated ill-defined of herterogeneous consistency as well as presence of gas pockets in the pancreatic and peri-pancreatic tissues, consistent with infected pancreatic necrotic collection in (A) and (B).Figure 2.: Image 2: Bibasilar lower lung infiltrates seen on CT scan chest (A) and Chest X-ray PA view (B), consistent with COVID-19 pneumonia.

S2589 A New Great Mimicker: A Rare Case of IgG4-Disease With Isolated Sclerosing Cholangitis

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a rare newly discovered systemic immune-mediated fibroinflammatory disease of unknown etiology that can involve multiple organs. IgG4-RD has a broad spectrum of entities. IgG4-related sclerosing cholangitis is the biliary manifestation of IgG4-RD, typically occurring together with type 1 AIP, but isolated IgG4-SC accounts for only 8% of IgG4-RD cases. Although the mainstay of IgG4-SC treatment is steroid (with and /or without immunosuppressants), but clinical studies are still scarce about this disease. CASE DESCRIPTION/METHODS: We present a rare and challenging case of a 60-year-old male who presented with steatorrhea and elevated liver enzymes without clinical signs of obstructive jaundice. Imaging revealed mild intrahepatic biliary ductal dilatation and mild wall thickening with no evidence of pancreatitis or mass. Esophagogastroduodenoscopy (EGD) and small bowel biopsy were unremarkable for malabsorption disorders. ERCP and EUS-FNA were inconclusive but excluded malignancy. However, a high index of suspicion for IgG4 has driven to check serology and surprisingly it has revealed a strongly elevated IgG4 level. The patient was started on steroid and later immunomodulator with subsequent clinical and serological improvement as well as resolution of the biliary ductal dilatation on imaging afterward.We here report a unique case of isolated IgG4-related sclerosing cholangitis with uncommon presentation and in the absence of AIP, diagnosed by clinical correlation, serology, response to steroids, and exclusion of other possible disorders. DISCUSSION: IgG4-RD is a newly recognized disease in the early 2000s, with unknown exact prevalence. The disease is difficult to diagnose and still does not have its own unique International Statistical Classification of Diseases and Related Health Problems (ICD)-10 code. IgG4-RD can mimic other autoimmune rheumatic diseases such as Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and granulomatosis with polyangiitis, as well as a number of other conditions. An isolated IgG4-SC may also mimic other conditions such as primary sclerosing cholangitis (PSC) and cholangiocarcinoma (CCA); therefore, physicians must carry a high index of suspicion for this under-recognized disease as IgG4-SC can respond to steroids in comparison to malignancy which is treated with surgical intervention. Early diagnosis and treatment are required to prevent irreversible fibrosis, biliary sepsis, and hepatic failure.Figure 1.: ERCP showing normal biliary tree with no focal lesions.

Type 1 Interferon Gene Signature Promotes RBC Alloimmunization in a Lupus Mouse Model.

Red blood cell (RBC) transfusion exposes recipients to hundreds of unmatched minor RBC antigens. This exposure can lead to production of alloantibodies that promote clinically significant hemolytic events. Multiple studies have reported an increased frequency of RBC alloimmunization in patients with autoimmunity. However, cellular and molecular mechanisms that underlie autoimmunity-induced alloimmunization have not been reported. Patients with systemic lupus erythematosus (SLE) have a high frequency of alloimmunization and express a type 1 interferon (IFNα/β) gene signature. Thus, we utilized the pristane-induced lupus mouse model to test the hypothesis that inflammation in lupus promotes RBC alloimmunization, and to examine the potential role of IFNα/β. Intraperitoneal injection of pristane, a hydrocarbon oil, led to autoantibody production, glomerulonephritis, and pulmonary hemorrhage in wild type (WT) mice. Pristane treatment significantly induced serum IFNα and expression of multiple interferon-stimulated genes (ISGs) in peripheral blood and peritoneal fluid cells, including inflammatory macrophages. Following transfusion with allogeneic RBCs expressing the KEL glycoprotein, pristane-treated WT mice produced significantly elevated levels of anti-KEL IgM and anti-KEL IgG, compared to untreated mice. Pristane induced comparable levels of inflammatory cells and cytokines in mice lacking the IFNα/β receptor (IFNAR1–/–) or the IFNα/β-inducing transcriptions factors (IRF3/7–/–), compared to WT mice. However, pristane-treated IFNAR1–/– and IRF3/7–/– mice failed to produce ISGs and produced significantly lower levels of transfusion-induced anti-KEL IgG, compared to WT mice. Thus, pristane induction of a lupus-like phenotype promoted alloimmunization to the KEL RBC antigen in an IFNα/β-dependent manner. To our knowledge, this is the first examination of molecular mechanisms contributing to RBC alloimmunization in a model of autoimmunity. These results warrant further investigation of the role of IFNα/β in alloimmunization to other RBC antigens and the contribution of the IFNα/β gene signature to the elevated frequency of alloimmunization in patients with SLE.

High-Dose Prednisone for Treatment of Autoimmune Pancreatitis in a Patient with Coronavirus Disease 2019 (COVID-19) due to Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Patient: Male, 53-year-oldFinal Diagnosis: Autoimmune pancreatitis type 1 • COVID-19Symptoms: Abdominal and/or epigastric pain • feverMedication: —Clinical Procedure: —Specialty: Gastroenterology and Hepatology • Infectious DiseasesObjective:Unusual clinical courseBackground:Autoimmune pancreatitis (AIP) is a rare, steroid-responsive disease of the pancreas. Concurrent treatment with immunosuppressants, including corticosteroids, increases the risk of developing a severe form of coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The World Health Organization (WHO) advises against the use of corticosteroids in patients with SARS-CoV-2 due to their poor outcomes in patients with SARS-CoV and Middle East respiratory syndrome (MERS-CoV), unless these patients require steroid treatment for a coexisting disease.Case Report:A 53-year old patient was admitted with symptoms and diagnostic findings consistent with AIP. Thorough etiological workup revealed an elevated IgG4 level of 361 mg/dL and significant clinical response to corticosteroid treatment, leading to a diagnosis of AIP. After finishing steroid treatment at home, the patient was readmitted with another episode of AIP complicated by development of acute necrotic collection and COVID-19 while taking a second course of high dose prednisone. The patient was continued on high dose prednisone, started on azathioprine and intravenous meropenem, and underwent CT guided percutaneous drainage. He also received supportive care for COVID-19. After significant clinical improvement, the patient was discharged to quarantine at home, which he completed uneventfully.Conclusions:Despite the use of corticosteroids due to AIP, this high risk patient recovered from COVID-19 without complications. These findings support the use of corticosteroids when necessary for treatment of coexisting conditions in COVID-19 patients.

Features of IgG4-related lung disease on 18F-FDG PET/computed tomography imaging.

The aim of the study was to summarize the features of immunoglobulin G4-related lung disease (IgG4-RLD) on fluorine 18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT). In this retrospective case series, 12 consecutive patients (9 men and 3 women, mean age 55.4 ± 13.7 years) with IgG4-RLD were included. The clinicopathological information and features of F-FDG PET/CT imaging were analyzed. Six (50%) patients had pulmonary involvement alone and six (50%) patients had extrapulmonary involvement with intense F-FDG uptake. Pulmonary manifestations included mass (25%, 3/12), solid nodule (solitary 25%, 3/12; multiple 50%, 6/12), multiple ground-glass opacities (GGOs) (50%, 6/12), thickening of alveolar interstitium (50%, 6/12), and thickening of bronchovascular bundle (33.3%, 4/12). The maximum standardized uptake value (SUVmax) of the solid nodules and masses, multiple GGOs, bronchovascular bundle and the thickening of septa was 4.0 ± 2.5, 2.3 ± 1.8, 1.4 ± 0.6, and 0.9 ± 0.5, respectively. The SUVmax statistically significant linear association with the diameter of masses or solid nodules (P value = 0.03), but no significant inverse linear association (P value = 0.06) with the concentration of serum IgG4 concentration. The image patterns of IgG4-RLD on F-FDG PET/CT are varying. Multiple pulmonary manifestations or multiple organ involvement, especially in combination with elevated levels of serum IgG and IgG4, may help to make the diagnosis. A potential major application of PET-CT would be evaluation of response to treatment, and the impact of PET/CT on IgG4-RLD management is worth investigating further in the future.