Extractable Nuclear Antigen Antibodies Research Articles

Retrospective analysis of the clinical significance of Ro52/TRIM21 antibody and specific antinuclear antibody patterns by indirect immunofluorescence.

To determine the clinical significance of Ro52 protein/tripartite motif-containing 21 antibody and specific antinuclear antibody patterns using indirect immunofluorescence technique. The retrospective study was conducted at the clinical laboratory of the First Affiliated Hospital of Chongqing Medical University, China, and comprised data from January 2017 to December 2021 of patients who underwent antinuclear antibody and anti-extractable nuclear antigen antibody detection. Inpatients with Ro52 antibody-positive status were taken as the cases, while anti-Ro52 negative patients with clear clinical diagnosis were taken as the controls. Data was analysed using SPSS 19. There were 1802 cases and 1211 controls. Positive Ro52 showed significantly greater frequency in patients with primary Sjogren's syndrome, systemic lupus erythematosus, inflammatory myositis, dry eyes and interstitial lung disease (p<0.05). Ro52 antibody showed high positive predictive value for primary Sjogren's syndrome 25(96.15%), systemic lupus erythematosus 259(91.20%), connective tissue disease-associated interstitial lung disease 45(86.67%) and inflammatory myositis 60(86.67%). Antinuclear antibody indirect immunofluorescence patterns most frequently detected were nuclear speckled 128(40.89%) and cytoplasmic speckled 126(40.26%) (p<0.05). Interstitial lung disease was associated with the presence of cytoplasmic speckled antinuclear antibody indirect immunofluorescence pattern 24(19.2%), while tumours 47(36.5%) and hepatitis B 26(20.3%) seemed to be more frequent with nuclear speckled pattern (p<0.05). The simultaneous reactivity extractable nuclear antigen antibodies most frequently detected were antinuclear antibody+Ro52+anti-Sjogren's syndrome A+ 558(33.96%). Ro52 antibody positivity was found to be associated with Sjogren's syndrome, systemic lupus erythematosus, inflammatory myositis, dry eye and interstitial lung disease. The antinuclear antibody immunofluorescence pattern of Ro52 positive was single and primarily granular cytoplasm type. Antinuclear antibody negative and Ro52 positive in the serum of patients also had certain significance in auxiliary disease diagnosis.

Spontaneous Iliac Artery Dissection in a 66-Year Old Male Complicated By Hemorrhage, GI Bleeding, and Bilateral DVT/PE

Spontaneous iliac artery dissection (IAD) is a rare medical condition with only a few cases being reported in the medical literature. Dissections typically involve the aorta and are not localized to the iliac arteries. Patients with spontaneous IAD typically present with symptoms that resemble peripheral artery disease, and cases are typically associated with connective tissue diseases such as Marfan syndrome and Ehlers-Danlos syndrome or high-risk states such as pregnancy and extreme athletics. There are some case reports that showed an association with hyperlipidemia, hypertension, and tobacco use. The most frequent complication of spontaneous IAD is rupture, and cases are typically treated endovascularly but may be treated with classical surgery such as in the case of rupture. Some cases have reportedly been treated with conservative management alone. In this case, we discuss a 66-year-old male with a past medical history of hyperlipidemia, hypertension, and tobacco use with no known diagnosis of connective tissue disease, and not in a high-risk state, who was found to have a spontaneous iliac artery dissection. He initially presented with sudden onset back pain that he described as a shooting pain that radiated into his head. He was also having right lower extremity discomfort. Initial vital signs were significant for tachycardia and hypertension, and physical exam was significant for tachycardia and diminished right posterior tibial and dorsalis pedis pulses. Laboratory workup was significant for a leukocytosis of 10.06 and creatinine of 1.52, consistent with acute kidney injury. Labs were otherwise unremarkable. Computed tomography angiogram (CTA) of the head and neck was negative for acute pathology, but CTA chest/abdomen/pelvis demonstrated arterial dissection that began at the origin of the right common iliac artery extending down to the right common femoral artery and also demonstrated a left renal infarct. A bare metal stent was placed by Interventional Radiology and the patient was started on dual antiplatelet therapy (DAPT) with a heparin drip and clopidogrel. Connective tissue disease workup was later performed including antinuclear antibody, rheumatoid factor, cyclic citrullinated peptide, and extractable nuclear antigen antibodies panel, which were all negative. Hospital stay was complicated by development of subarachnoid hemorrhage, intraventricular hemorrhage, subdural hematoma, and intradural hematoma that required laminoplasty and evacuation by Neurosurgery. DAPT was discontinued and the patient was later restarted on aspirin only. The patient then developed a cecal bleed that required clipping by Gastroenterology. Aspirin was discontinued and he then developed bilateral lower extremity deep venous thromboses and pulmonary emboli. He was started on enoxaparin with the assistance of Hematology and was later transitioned to apixaban with no complications. This case supports comorbidities as risk factors for spontaneous IAD and raises the need for formal screening and surveillance guidelines for these patients, as there are currently no guidelines in place. This case also demonstrates the complications that can occur with DAPT and anticoagulants and provides a manner in which to cautiously initiate anticoagulation in patients with high risk of bleeding while also preventing the development of further thrombi.

Antinuclear Antibodies Are Associated with an Increased Risk of Diffuse Large B-Cell Lymphoma.

Immune dysregulation is thought to increase the risk of non-Hodgkin lymphoma (NHL), but the evidence varies by subtype. We evaluated whether antinuclear antibodies (ANA), double-stranded DNA antibodies (anti-dsDNA), and extractable nuclear antigen antibodies (anti-ENA) were associated with the risk of common NHL subtypes in a nested case-control study. The autoantibodies were tested in serum collected years prior to NHL diagnosis in 832 cases and 809 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Logistic regression was used to determine odds ratios (ORs) and 95% confidence intervals (95% CI) for the association with NHL risk. No association was observed between ANA positivity and NHL risk overall (OR: 1.18, 95% CI: 0.88-1.58); however, ANA positivity was associated with an increased risk of diffuse large B-cell lymphoma (DLBCL) (OR: 1.83, 95% CI: 1.15-2.91), with 19.7% of cases and 12.2% of controls testing positive. The presence of either anti-ENA or anti-dsDNA was associated with an increased risk of NHL (OR: 2.93, 95% CI: 1.18-7.28), particularly DLBCL (OR: 3.51, 95% CI: 1.02-12.0) and marginal zone lymphoma (OR: 8.86, 95% CI: 1.26-62.0). Our study demonstrates that autoantibodies are associated with an elevated risk of DLBCL, providing support for autoimmunity as a risk factor.

Five-Year Analysis of Anti-Nuclear Antibody (ANA) and Extractable Nuclear Antigen Antibody (anti-ENA) Immunoblot Test Results

Autoimmune disorders may cause systemic disease in which multiple organs are affected or may also be localized as single-organ involvement. Various ancillary immunological tests used in cases where systemic involvement is observed, and differential diagnosis becomes difficult or non-specific symptoms are observed. For this purpose, investigation of antinuclear antibodies (ANA) and antibodies against extractable nuclear antigens (ENA) in patient serums using various methods is a guide for clinicians. In this study, we aimed to evaluate the effectiveness of ANA and ENA antibody tests by examining the test results, the patients’ demographic data, and the clinics that ordered the tests. In the study, a retrospective review of the results of 37,791 ANA tests studied on serum samples sent to the medical microbiology laboratory of our hospital from various clinics between January 2018 and December 2022 is presented. ANA tests were resulted semi-quantitatively by evaluating the slides prepared using diluted serum samples at a ratio of 1:100 and HEp-2 cells and monkey liver tissue under a fluorescent microscope with the indirect immunofluorescence (IIF) antibody method. Of the patients who requested ANA test, 11,604 (30.7%) were male and 26,187 (69.3%) were female. The mean ages were 43.46 (0-94) and 46.94 (0-96), respectively. Of the samples tested, 18.8% (7,107/37,791) were evaluated as ANA positive. The ANA positivity rate was significantly higher in women (24.8%) than in men (19.7%) (p&lt;0.001). ANA positive samples were re-tested using the anti-ENA immunoblot method. Of the 7,107 ANA-positive patients, 3,809 (53.6%) were found to be anti-ENA positive for at least one specific antibody, while 3,298 (46.4%) were negative. In the anti-ENA profile, antibodies against 11 different antigen types were screened and the most frequently detected antibody was anti-SS-A (22.7%), and this was followed by anti-centromere (12.8%), anti-RNP (10.2%), and anti-dsDNA (9.7%) antibodies. Immunoblot-based anti-ENA tests provide specific information for the diagnosis of autoimmune diseases. In our study, the fact that anti-ENA tests were negative in a significant part of ANA positive patients indicates the inadequacy of the immunoblot test panel and reveals the need for immunoblot tests with wider antibody diversity or any alternative methods.

Increased carotid intima–media thickening and antioxidized low-density lipoprotein in an anti-Ro60 SLE autoantibody subset

ObjectivePremature atherosclerosis is associated with systemic lupus erythematosus (SLE). We have previously shown an association of anti-Ro60/La/Ro52 with antioxidized low-density lipoprotein (LDL) in SLE. Here, we hypothesized that carotid intima–media thickening (CIMT) would be associated with antioxidized LDL (anti-oxLDL)/antilipoprotein lipase (ALPL) in a specific SLE autoantibody subset (anti-Ro60 positive, anti-RNP positive, anti-SmRNP positive, or extractable nuclear antigen antibody negative).MethodsWe carried out a case-control study (one time-point testing) of CIMT, ALPL, anti-oxLDL, anti-low density lipoprotein (ALDL), and anti-LDL in 114 SLE patients and 117 age/sex-matched controls. The levels of total cholesterol, LDL, high-density lipoprotein (HDL), triglycerides, and HDL-Trig were also measured. A student's t-test was used for statistical analysis.ResultsInterestingly, the level of CIMT was highest in the SLE subset with anti-Ro60 (23/114). CIMT and anti-oxLDL were statistically significantly elevated in the anti-Ro60 SLE subset (1.3 ± 1.66, p &amp;lt; 0.01; 0.26 ± 0.16, p &amp;lt; 0.002, respectively) compared with controls (0.54 ± 1.26; 0.165 ± 0.13, respectively), but not anti-LPL/anti-LDL. CIMT was significantly elevated (0.9 ± 1.71; p &amp;lt; 0.05) in the SLE subset without antiextractable nuclear antigen (ENA) (63/114) compared with controls. The other antibodies in this subset were not statistically different from other SLE subsets or controls. Only antioxLDL was significantly elevated (0.29 ± 0.27; p &amp;lt; 0.005) in the SLE subset with anti-RNP (14/114) compared with controls, while none were elevated in the anti-SmRNP subset (6/114). We did not find any significant differences in lipids between the various SLE subsets.ConclusionCIMT segregates in anti-Ro and ENA negative groups either with or without anti-oxLDL. It will be clinically important if cardiovascular events are augmented in the SLE anti-Ro subset having elevated antioxidized LDL antibodies.

Long-term presence of autoantibodies in plasma of cured leprosy patients

Autoantibodies have been detected in leprosy patients, indicating that infection with M. leprae may lead to autoimmune disorders. However, whether autoimmune response last until patients are cured is unknown. Knowing the autoimmune response in cured leprosy patients is essential to identify whether symptoms are caused by leprosy itself or by other immune-related diseases. This knowledge is essential for the ongoing health management in cured leprosy patients where autoimmune disorders still exist. In our study, we selected six autoantibodies, including anticardiolipin antibody of IgG (ACA), anti-nuclear antibody (ANA), extractable nuclear antigen antibody (ENA), anti-streptolysin O (ASO), anti-double stranded DNA antibody (dsDNA), and rheumatoid factor (RF), that had been reported in leprosy patients as typical autoantibodies. We tested the six typical autoantibodies combined with LACC1, which encodes a protein associated with autoimmune disease such as Crohn’s disease and is also the susceptible gene conferring leprosy risk, in cured leprosy patients through ELISA to assess the cured patient’s immune status. We observed high positive rates of autoantibodies in cured leprosy patients, and the average plasma levels of five (ACA, ANA, ENA, ASO, and RF) out of the six autoantibodies were significantly higher in cured leprosy patients than in controls. The positive detection of autoantibodies is independent of the recovery period. Moreover, the level of these autoantibodies showed a strong positive correlation with the level of LACC1 in both controls and cured patients. This study showed that there is long-term autoimmunological activation in leprosy patients, even after decades of recovery. Autoimmune responses may influence the development and prognosis of leprosy. Special care should be given to posttreatment or cured leprosy patients regarding long-term autoimmunological activation.

An Unusual Case of Intermittent Fever With Multiple Liver Lesions

Question: A 46-year-old man with a history of hypertension presented to our hospital with a chief compliant of intermittent fever for 2 weeks. He denied a history of nausea, vomiting, abdominal pain, diarrhea, abdominal distention, loss of appetite, or weight loss. Physical examination on admission was unremarkable. Laboratory studies showed white blood cells 15.32 × 109/L (reference 3.5–9.5 × 109/L) with 38.3% (reference 0.4%–8.0%) eosinophils, C-reactive protein 49.72 mg/L (reference 0–10 mg/L), and erythrocyte sedimentation rate 44 mm/h (reference 0–15 mm/h). No parasite eggs or larvae were found in microscopic examination of direct smears of the stool. Liver function tests revealed alanine transaminase 50.5 IU/L (reference 9–50 IU/L), alkaline phosphatase 134 IU/L (reference 15–40 IU/L), gamma-glutamyltransferase 224 IU/L (reference 10–60 IU/L), total protein 40.1 g/L (reference 65–85 g/L), and albumin 21.6 g/L (reference 40–55 g/L). His renal function and tumor markers, such as alpha-fetoprotein, carcino-embryonic antigen, and carbohydrate antigen 19-9 were all within normal ranges. Tests for hepatitis B, hepatitis C, antinuclear antibodies, extractable nuclear antigen antibodies, and anti–neutrophil cytoplasm antibodies were all negative. No significant abnormalities were detected on electrocardiography, echocardiography, and chest computed tomography (CT). Routine ultrasound revealed multiple hypoechoic areas with unclear borders in the left lobe and right posterior lobe of the liver. Magnetic resonance imaging (MRI) of the liver was subsequently performed and showed multiple nodular or clumpy lesions as low signal intensity on T1-weighted imaging (WI) (Figure A) and high signal intensity on fat-suppressed T2-WI (Figure B) and diffusion WI (Figure C). Contrast-enhanced scan exhibited slightly heterogeneous enhancement (Figure D) or annular enhancement (Figure E). MRI did not indicate any anatomic malformations or intrahepatic or extrahepatic bile duct dilation. Positron emission tomography–computed tomography (PET-CT) revealed increased 18F-fluorodeoxyglucose uptake in the liver lesions (maximum standardized uptake value 3.8–5.2) (Figure F). The patient subsequently underwent CT-guided liver biopsy. Histopathology demonstrated chronic hepatic inflammation with prominent eosinophilic infiltration in portal areas and some acinar areas (Figure G).

PD-1/PD-L1 immune-checkpoint blockade induces immune effector cell modulation in metastatic non-small cell lung cancer patients: A single-cell flow cytometry approach.

Peripheral immune-checkpoint blockade with mAbs to programmed cell death receptor-1 (PD-1) (either nivolumab or pembrolizumab) or PD-Ligand-1 (PD-L1) (atezolizumab, durvalumab, or avelumab) alone or in combination with doublet chemotherapy represents an expanding treatment strategy for metastatic non-small cell lung cancer (mNSCLC) patients. This strategy lays on the capability of these mAbs to rescue tumor-specific cytotoxic T lymphocytes (CTLs) inactivated throughout PD-1 binding to PD-L1/2 in the tumor sites. This inhibitory interactive pathway is a physiological mechanism of prevention against dangerous overreactions and autoimmunity in case of prolonged and/or repeated CTL response to the same antigen peptides. Therefore, we have carried out a retrospective bioinformatics analysis by single-cell flow cytometry to evaluate if PD-1/PD-L1-blocking mAbs modulate the expression of specific peripheral immune cell subsets, potentially correlated with autoimmunity triggering in 28 mNSCLC patients. We recorded a treatment-related decline in CD4+ T-cell and B-cell subsets and in the neutrophil-to-lymphocyte ratio coupled with an increase in natural killer T (NKT), CD8+PD1+ T cells, and eosinophils. Treatment-related increase in autoantibodies [mainly antinuclear antibodies (ANAs) and extractable nuclear antigen (ENA) antibodies] as well as the frequency of immune-related adverse events were associated with the deregulation of specific immune subpopulations (e.g., NKT cells). Correlative biological/clinical studies with deep immune monitoring are badly needed for a better characterization of the effects produced by PD-1/PD-L1 immune-checkpoint blockade.

Renal Transplantation in Pure Autonomic Failure.

Renal Transplantation in Pure Autonomic Failure.

Low Prevalence of Anti-DFS70 Antibodies in Children With ANA-Associated Autoimmune Disease.

IntroductionAnti-DFS70 antibodies occur in healthy individuals with various medical conditions. Unlike other anti-nuclear autoantibodies (ANA), they are not associated with systemic autoimmune disease in adult patients. To date, only a few studies have addressed the prevalence and/or clinical relevance of anti-DFS70 autoantibodies in children with and without autoimmune disease.MethodsIncluded in this retrospective cross-sectional mono-centric study were 308 pediatric patients with suspected or known autoimmune conditions who had a positive ANA in indirect immune fluorescence (IIF) screening and who were screened for anti-DFS70 antibodies by extractable nuclear antigen antibodies (ENA) immunoblot. Patients were assigned to four different diagnostic categories according to their diagnosis in the corresponding medical record: (a) absence of autoimmune or rheumatic disease (noARD, n = 116); (b) suspected autoimmunity without definitive diagnosis (sAI, n = 48); (c) other rheumatic disease (ORD) (n = 115); and (d) ANA-associated autoimmune disease (AARD, n = 29).ResultsThe prevalence of anti-DFS70 antibodies in the overall cohort was 33.8%. Among children without ARD (46.6%, 54/116), prevalence was significantly higher than among children with ORD (23.7%, 27/115, p = 0.0003) or AARD (17.2%, 5/29, p = 0.0054). Among all of the anti-DFS70 positive patients with AARD, other autoantibodies were found in the ENA immunoblot. In contrast, among anti-DFS70 positive patients with ORD (11.5%, 4/27), sAI (33.3%, 6/18) and noARD (16.7%, 9/54), other autoantibodies infrequently were detected (p = 0.0005). Patients with uveitis rarely were positive for anti-DFS70 antibodies (7.7%, 1/13). No association was found between anti-DFS70 antibodies and a history of allergic conditions (p = 0.51). The concordance between a typical DFS pattern in IIF and the detection of anti-DFS70 antibodies by immunoblot was 59.3%.ConclusionAs with adults, the higher prevalence of anti-DFS70 among children without autoimmune disease confirms the mutual exclusion for this autoantibody in the pathogenesis of ARD. Among ANA-positive children, monospecific anti-DFS70 antibodies may help to discriminate between AARD and not-AARD-related conditions.

Investigation of the Contribution of Autoantibodies to Clinical Diagnosis in Liver Pathologies and the Identification of Accompanying Autoimmune Diseases

Autoantibodies are frequently detected in the presence of autoimmune liver diseases (ALD) [autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)] and are widely used to classify the disease clinically. The aim of this study was to investigate the contribution of autoantibodies for the diagnosis of ALD and the identification of other accompanying systemic autoimmune rheumatic diseases (SARD). In addition, it was aimed to compare the results of indirect immunofluorescence (IIF) antinuclear antibody (ANA) patterns and extractable nuclear antigen (ENA) antibodies. A total of 593 patients, including 544 patients with high liver function tests from general surgery/gastroenterology clinics and 49 patients referred from internal medicine/rheumatology clinics to investigate ALD, were included in the study. HBsAg and anti-HCV test results of the patients were found to be negative. ANA, anti-mitochondrial antibody (AMA)/anti-liver-kidney microsomal antibody (LKM), anti-smooth muscle antibody (ASMA), antineutrophil cytoplasmic antibody (ANCA) assays were performed by indirect immunofluorescence method (IIF) (Euroimmune AG, Luebeck, Germany). Extractable nuclear antigen (ENA) (nRNP/Sm, Sm, SS-A, SS-B, Scl-70, Jo-1, dsDNA, nucleosome, histone, ribosomal P-protein, AMA-M2, Ro-52, PM-Scl, CENP-B, PCNA, DFS70) and liver profiles [soluble liver antigen\liver pancreas antigen (SLA/LP), liver cytosolic antigen1(LC-1), LKM-1, anti-mitochondrial antibody M2(AMA-M2)] (Euroimmune AG, Luebeck, Germany) were detected by immunoblot (IB) method. Demographic characteristics, clinical data, presence of systemic autoimmune rheumatic diseases (SARD), radiological and laboratory findings were determined from the medical records. Autoantibody tests were found to be negative in 461 (77.7%) of 593 patients (mean age= 53.3 ± 15.6, age range= 18-90), and were positive in 132 (22.3%) (86.4% female) of the patients. Of the patients with positive autoantibodies, 60.6% (80/132) were diagnosed as PBS and 1.5% (2/132) were diagnosed as AIH (positive anti-LC-1 and anti-LKM1 antibodies). Fourteen of the patients (10.6%) with centromere, nuclear membrane (NM), multiple nuclear dot (MND) staining patterns and elevated liver enzymes could not be diagnosed as a specific disease and were followed up. PBS (13/30) was detected in approximately half of the patients diagnosed with SARD. The most common accompanying SARD in PBC patients was Sjögren's syndrome (SS) (7.5%, 6/80), followed by rheumatoid arthritis (RA) (5.0%, 4/80), scleroderma (2.5%, 2/80), and systemic lupus erythematosus (SLE) (1.3%, 1/80) respectively. The most common pattern was the AMA staining pattern (34.8%, 46/132) among the autoantibody positive patients. AMA and ANA staining patterns were detected together in 31.1% (41/132) of the patients. In the ENA profile results of these patients, the most common profile detected was anti-Ro-52 (65.9%, 27/41), followed by anti-SSA (34.1%, 14/41), anti-SSB (22.0%, 9/41) and anti-CENP-B (12.2%, 5/41) autoantibodies , respectively. ANA patterns were detected in 32.6% (43/132) of the patients (NM 9.1%, centromere 9.1%, MND 6.8%, respectively). In our study, 87.5% (70/80) of the patients diagnosed as PBS were found to have AMA positivity and 12.5% (10/80) of them had ANA positivity (such as NM, CNN, centromere). The characteristics, laboratory and radiological findings of the patients with isolated AMA positivity alone (Group 1) and patients with multiple patterns/autoantibodies (Group 2) were compared. In patients with multiple patterns/autoantibodies (Group 2), the presence of cirrhosis and liver heterogeneity were found to be higher than Group 1 (p= 0.049). ALD associated autoantibodies can be detected before years from the clinical disease. ALD may be associated with various SARD. Detection of ALD-related autoantibodies in patients diagnosed with SARD can provide early diagnosis of these patients. These autoantibodies guide both diagnosis and prognosis as in PBC. Collaboration between the laboratory specialist and the clinician is critical in the diagnosis, management and early recognition of these patients before clinical disease.

Dense fine speckled immunofluorescence pattern in a Chinese population: Prevalence and clinical association.

ObjectiveTo provide information on the prevalence and possible clinical association in a Chinese population for medical practice of the dense fine speckled pattern (DFS pattern).MethodsA retrospective study was conducted with patients who had the DFS pattern from June 2018 to December 2019 in West China Hospital.ResultsA total of 469 patients (1.27% of patients with positive anti‐nuclear antibody indirect immunofluorescence (ANA IIF) test results) revealed the DFS pattern, of which 92.96% had isolated DFS pattern and 23.67% had titers above/equal to 1:320. The average age of patients with the DFS pattern was 43.45 years, and females accounted for 76.97% of them. Ten different kinds of diseases made up the vast majority of the disease spectrum, in which inflammatory or infectious diseases (46.11%), mental diseases (21.45%), and systemic autoimmune rheumatic diseases (SARDs) (18.23%) ranked in the top three. The most common SARDs were rheumatoid arthritis (RA), undifferentiated connective tissue disease (UCTD), and systemic lupus erythematosus (SLE). Forty‐six patients (10.55%) had positive or suspicious extractable nuclear antigen (ENA) antibodies test results and a higher risk of suffering from SARDs. Forty‐seven patients would be missed if the DFS pattern with negative ENA antibodies test result was considered as exclusion criterion of SARDs.ConclusionsThe DFS pattern is basically isolated and with low titer. It is unwise to exclude the diagnosis of SARDs only depending on the appearance of the DFS pattern. Autoimmune diseases‐related antibodies, clinical information of patients, and long‐term follow‐up are of great importance to avoid missed or delayed diagnosis of SARDs.

O30 Case report of Cogan syndrome in a child with audiovestibular dysfunction and ocular inflammation

Case report - IntroductionCogan syndrome is a very rare disorder of probable autoimmune vasculitic origin, first described in 1934. The age of onset seems to range from 3 to 50 years with an average age of disease onset at 29 years. It is characterised by audiovestibular dysfunction and ocular inflammation. The cause remains unknown and the epidemiology of the disease is purely based on case reporting. As of 2015, there were fewer than 250 case reports. Interestingly, it seems extremely rare in Arabic and Middle Eastern countries in which a new case has been recently diagnosed and is being reported in this abstract.Case report - Case descriptionA 14-year-old girl of Arabic origin first presented to the ENT specialist with a 3-week history of balance problems, left tinnitus and sensorineural hearing loss in both ears worse on the left. She first received treatment for vestibular neuritis with no improvement. Two months later, she complained of bilateral red eyes and excessive lacrimation when diffuse interstitial keratitis was diagnosed by the ophthalmologist. An array of blood tests including a full autoimmune disease was arranged and a rheumatology opinion was sought.The patient had a normal inflammatory response and her screen for antinuclear antibodies, extractable nuclear antigen, rheumatoid factor and antineutrophil cytoplasmic antibodies were all negative. A full virology screen was also negative. Having failed to respond to all supportive treatment modalities, a trial of a tapering 2-week course of prednisolone starting at 25mg daily was instigated. The patient’s symptoms improved by more than 50% on glucocorticoids subsequent to which the diagnosis of Cogan syndrome was anticipated. As the patient’s symptoms relapsed when glucocorticoids were stopped, she was recommenced on prednisolone 25mg in line with azathioprine 100mg daily. The patient’s hearing, which was almost lost in the left ear, improved significantly by more than 70% initially, and then to normal hearing as stated by the patient supported by special ENT testing. Her balance problems and vertigo also improved remarkably. Her tinnitus, which was the last symptom to resolve, almost went away over the subsequent 2 months. The patient had already come off glucocorticoids 6 months down the line, and stayed on azathioprine 75-100mg daily for almost a year after which gradual weaning was trialled and then eventually succeeded. She has now been off azathioprine for 6 months without experiencing any disease relapse.Case report - DiscussionCogan syndrome can be difficult to diagnose particularly in children. The diagnosis is essentially clinical depending on the presence of audio-vestibular symptoms and interstitial keratitis along with a prompt response to immunosuppressive medication.In this patient, the consistent clinical picture supported by the positive response to glucocorticoids especially in the absence of an alternative diagnosis would have made the diagnosis of Cogan syndrome likely.Given the rarity of this disorder, there are no classification criteria as yet hence the ongoing need for case reporting. Moreover, there is no clear guidance on the duration of immunosuppressive treatment of this condition.Case report - Key learning pointsIt is pivotal in managing conditions with a suspected autoimmune origin to have a multidisciplinary approach involving other relevant specialties in a holistic approach.The prompt response to glucocorticoid therapy still remains the key in securing the diagnosis of a number of conditions in clinical practice especially in the absence of diagnostic criteria and/ or supportive investigations such as serological and tissue-based testing.Case reporting has a crucial role in enhancing awareness of rare medical conditions.

Associations between sarcoidosis, autoimmune diseases, and autoantibodies: a single-center retrospective study in China

To describe the clinical manifestations, immunological features, and risk factors in patients with sarcoidosis complicated with autoimmune diseases (ADs) as well as determine the frequency of autoantibodies and possible correlation between autoantibodies and laboratory data. Patients with pathologically confirmed sarcoidosis at Beijing Chaoyang Hospital (China) between January 2017 and October 2020 were included. Age- and sex-matched patients who visited the rheumatology outpatient clinic without systemic or ADs were included as controls. Demographic, clinical, serological, and radiological data of sarcoidosis patients were recorded and analyzed. To exclude ADs, autoantibodies, such as antinuclear antibody, extractable nuclear antigen antibodies, and anti-cyclic citrullinated peptide antibody were assessed in controls. A total of 154 sarcoidosis patients (111 females; 72.1%) with a mean ± standard deviation age of 50.7 ± 10.3years were included. Nineteen patients (12.3%) had ADs; Hashimoto's thyroiditis (n = 6) and Sjogren's syndrome (n = 4) were common. Age, globulin, immunoglobulin G, erythrocyte sedimentation rate (ESR), and C-reactive protein were significantly different between sarcoidosis patients with and without ADs. The ESR level might be a risk factor for sarcoidosis complicated with ADs (RR = 1.053; P = 0.018). Autoantibodies were detected in 29 patients (18.8%), and the frequency was significantly higher than that in controls (18.8% vs. 3%; P = 0.001). Sarcoidosis patients were more likely to have autoantibodies despite the absence of ADs (10.4% vs. 3%; P = 0.031). Age may be a risk factor for sarcoidosis patients presenting with autoantibodies (RR = 1.077; P = 0.042). An association was identified between ADs and sarcoidosis. The inflammatory indexes, such as ESR, IgG, and CRP, were significantly different between sarcoidosis patients with and without ADs. ESR might be a risk factor for the coexistence of ADs and sarcoidosis. Sarcoidosis patients were prone to being autoantibody-positive despite the absence of ADs, and age might be a risk factor for sarcoidosis presenting with autoantibodies.

AB0769 EROSIVE SYNOVITIS, DACTYLITIS, HYPERCALCAEMIA, LYMPHADENOPATHY, ELEVATED SERUM ACE &amp; HYPOTHYROIDISM – AN UNUSUAL PRESENTATION OF IGG4-RELATED DISEASE

Background:IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder which can affect almost any tissue in the body. We describe a challenging case of IgG4-RD which reflects the great heterogeneity of this disease.Objectives:A 49-year-old Mauritanian gentleman was referred to Rheumatology with chronic progressive symmetrical synovitis affecting the upper and lower limbs. He had no features suggestive of a spondyloarthropathy or connective tissue disease. Blood tests revealed a raised C-reactive peptide (CRP) of 194 mg/L and erythrocyte sedimentation rate (ESR) of 46 mm/hr. His rheumatoid factor and anti-cyclic citrullinated peptide antibodies were negative. Anti-nuclear antibody was weakly positive at 1:80 with a speckled pattern, but extractable nuclear antigen antibodies, anti-double-strand DNA-antibodies and anti-neutrophil cytoplasm antibodies were negative. Complement proteins and creatine kinase were normal. Radiographs of the hands and feet demonstrated widespread erosive changes worst at the metacarpophalangeal, metatarsophalangeal and first tarsometatarsal joints, as well as swan-neck deformities of the fifth phalanges in both hands. Chest radiograph and serological virology screen were both unremarkable. He was subsequently diagnosed with a seronegative inflammatory arthritis and treated with intramuscular methylprednisolone. He was awaiting subcutaneous methotrexate.Methods:He was hospitalised shortly after with worsening polyarthritis and hypercalcaemia (3.34 mmol/L). Examination demonstrated synovitis, new lymphadenopathy and dactylitis. Other investigations revealed a normocytic anaemia (Hb 80 g/dL, MCV 80 fL), neutrophilia (20 x 109/L), eosinophilia (4 x 109/L), thrombocythaemia (500 x 109/L), hypoalbuminaemia (25 g/L), CRP 200 mg/L and ESR 60 mm/hr. All immunoglobulins were raised with IgG 30.5 g/L. IgG4 subset was 3.0 g/L. Parathyroid hormone was low (&lt; 0.7 pmol/L) and vitamin D was 125 nmol/L. Thyroid function, myeloma screen and blood tumour markers were unremarkable. Blood film revealed no blasts. Serum angiotensin-converting enzyme (ACE) was elevated at 171.9 U/L. A CT-chest-abdomen-pelvis revealed an enlarged thyroid with retrosternal extension and widespread lymphadenopathy above the diaphragm.Results:Biopsies of the thyroid gland and submandibular lymph node demonstrated lymphoplasmacytic fibroinflammatory changes and &gt; 40% of IgG4 cells. Neither biopsy showed evidence of sarcoidosis, tuberculosis or malignancy. He was treated with a weaning regimen of high-dose oral corticosteroids resulting in normalisation of haematological, inflammatory and biochemical parameters. His musculoskeletal pain, swelling and early morning stiffness significantly improved too. Subcutaneous methotrexate was commenced and titrated upwards to 20 mg. Two months later, his arthritis relapsed upon reduction of corticosteroids. Again, there was a marked inflammatory response with raised CRP and ESR. He had also developed a new hypothyroidism (TSH &gt; 100 mU/L, T4 0.5 µg/dL, positive TPO-antibody). Repeat hand and feet radiographs revealed severe erosive progressive disease (Figure 1). He awaits commencement of rituximab.Figure 1.Plain hand radiograph demonstrating extensive erosive arthritis.Conclusion:This is a unique presentation for a rare disease. There are few case reports of IgG4-RD causing erosive synovitis with rheumatoid-like swan-neck deformities or hypercalcaemia. Furthermore, this is the first case report as far as we know, of the disease associated with dactylitis or a raised serum ACE. Prior to biopsy, our main working diagnoses were sarcoidosis or a lymphoproliferative malignancy. The peculiar presentation necessitated a second opinion via the national IgG4-RD MDT who confirmed the histological diagnosis of IgG4-RD. We hope that this interesting case highlights the importance of histology in diagnosis of complex cases. In addition, the case presentation adds to the multitude of clinical manifestations of IgG4-RD.Disclosure of Interests:None declared

Graves’ Disease and Evans’ Syndrome as First Manifestation of Systemic Lupus Erithematosus

Abstract Background: Graves’ disease is the most common cause of hyperthyroidism triggered by antibodies called thyroid-stimulating immunoglobulin (TSI) which stimulates an overproduction of thyroid hormones. Evans’ syndrome is a rare condition characterized by autoimmune hemolytic anemia and immune thrombocytopenic purpura. Systemic lupus erythematosus (SLE) is also an autoimmune disease with extreme heterogeneity and potentially involvement of any organ or system. It is well known when a patient is diagnosed with an autoimmune disease, it is about time to show up other manifestations of another one, just as it happened in this case report. Clinical Case: A 31-year-old pregnant woman (22 weeks) was admitted to the obstetric emergency room due to headaches, weakness and tinnitus. During anamnesis, she said she was diagnosed with hypertension several weeks before she was pregnant. At physical examination, a 160/100 mm/Hg blood pressure and a heart rate over 100 bpm were found. Initial tests were solicited congruent with severe thrombocytopenia (20 000/mm3) and severe anemia (6 gr/dl), there was also a modest increase in transaminases levels. Transfusion support was needed and a “HELLP syndrome” was diagnosed. Gynecologists decided to perform an emergency hysterotomy and the end of pregnancy. During the post-operative care and the following days, the patient persisted with an average of 100 bpm heart rate and hypertension despite of the use of antihypertensive medication. Physicians also noticed the presence of malar rash and goiter. Thyroid hormones levels where requested and the results were consistent with primary hyperthyroidism (TSH: &amp;lt;0.005 Mu/L, FT4: &amp;gt;100 pmol/L). Further tests were required such as TSI (positive), a thyroid scintigraphy (high thyroid uptake), antinuclear antibodies (ANA: + 1/160 speckled pattern, anti- Smith: +) and extractable nuclear antigen antibodies (ENA) panel. Grave’s disease and SLE were diagnosed. Rheumatologists suggested that the diagnosis of HELLP Syndrome was unclear and they strongly believed that thrombocytopenia and anemia during pregnancy were part of Evans’s syndrome and at the same time of SLE. Antithyroid drugs (thiamazol), beta blockers (propranolol) hydroxychloroquine and corticoids (prednisone) were given to the patient with an excellent clinical and biochemical response. Conclusion: A 25% of patients with SLE can be diagnosed with an autoimmune thyroid disease, such as Graves’ disease (1). Frequent evaluation of thyroid hormones and antithyroid antibodies should be performed in patients with SLE, especially when there are related symptoms of a thyroid disorder.

The Forgotten Story of Vitamin C Deficiency

Vitamin C plays an essential role in the formation of collagen. A deficiency in vitamin C can lead to scurvy, manifested by blood vessel fragility, fatigue, and, rarely, death. Today, scurvy is rare in developed countries. Therefore, to diagnose scurvy requires a high index of suspicion. This will be illustrated by our patient of interest. A 66-year-old man presented to the emergency department (ED) with worsening bilateral leg swelling and bruising throughout his body. His past medical history was notable for a bowel resection with colostomy secondary to colorectal cancer, currently in remission. The bruising and swelling began two weeks prior without any inciting events. He denied taking blood thinners or non-steroidal-anti-inflammatory-drugs. He had no personal or family history of bleeding disorders. None of his previous surgeries were complicated by bleeding issues. Extremities showed large ecchymoses over left thigh and bilateral ankles, and hematoma over right patella. There were no perifollicular hemorrhages seen on skin examination. His hemoglobin was 13.5 g/dL and his platelet count was 145x109/L. A computed tomography angiography of his lower extremities revealed intramuscular hematomas in the calves, left adductor compartment and left sartorius. A venous ultrasound of bilateral lower extremities was unremarkable. He was advised to follow up with a hematologist outpatient. Ten days later, the patient reported worsening swelling and pain of his lower extremities and was advised to visit the ED (FIGURE 1A). His Hgb dropped to 10.8 g/dL. An extensive factor workup showed: factor VIII activity of 421.7% (ref range: 55-200), factor IX activity of 104% (ref range: 70-130), factor XI activity of 68% (ref range: 55-150), and von Willebrand factor activity of 355% (ref range: 55-200). Factor V, X and XIII were within normal limits. Other possible etiologies including vitamin K, HIV, hepatitis panel, antinuclear antibody and extractable nuclear antigen antibodies panel were normal. His activated partial thromboplastin time (aPTT) was prolonged at 44 seconds (ref range 25-37). The dilute Russel's viper venom time (dRVVT) was abnormal and his dRVVT/dRVVT-phospholipid ratio was greater than 1.3 or greater, indicative of a lupus anticoagulant. Beta-2 glycoprotein 1 antibodies and anticardiolipin antibodies were normal. Bleeding due to prothrombin (factor II) deficiency in the context of lupus anticoagulant has been reported (2). However, his factor II level was normal. Meanwhile, his Hgb fell to 6.9 g/dL, indicative of ongoing intramuscular bleeding. Upon further investigation by the consulting hematology team and registered dietitian, there was a concern for severe malnutrition, evident by substantial loss of subcutaneous fat and muscle mass. The patient revealed that he consumed six twelve-ounce cans of beers nightly. His diet was minimal in fruits and vegetables. One month prior to his admission, he had worsening fatigue, brittle nails and gum bleeding. His folate level was 2.0 ng/mL (ref range &amp;gt;3.9) and his albumin level dropped to 2.1 g/dL (ref range 3.5-5). His vitamin C level resulted &amp;lt; 0.1 mg/dL (ref range 0.4-2). He was started on three days of intravenous vitamin C, one gram per day. His hematoma and bruises dramatically improved (FIGURE 1B). As a result, a diagnosis of scurvy was made. On discharge, he was transitioned to oral vitamin C and advised to follow up with his hematologist outpatient. Scurvy is often viewed as a disease of the past. Yet, according to a national survey between 2003 and 2004, the prevalence of age-adjusted vitamin C deficiency is 7%. At risk patients include the elderly, institutionalized populations, alcoholics, and severe psychiatric illness leading to poor nutritional intake. Therefore, a dietary history of the patient should be obtained. Vitamin C contributes to the structure of blood vessels through its involvement in collagen synthesis. Characteristic signs and symptoms of scurvy feature fatigue, oral findings (spontaneous bleeding, gum retraction) and cutaneous abnormalities (petechiae and lesions). Rarely, it can lead to spontaneous intramuscular hematoma. The prognosis of scurvy is excellent, and the response to vitamin C is dramatic. This case illustrates the need to consider scurvy in diagnosing bleeding cases. A high index of suspicion remains integral in diagnosing scurvy to avoid expensive and lengthy workup. Disclosures No relevant conflicts of interest to declare.

Autoimmunity Features in Patients With Non-Celiac Wheat Sensitivity.

Nonceliac wheat sensitivity (NCWS) is characterized by intestinal and extraintestinal manifestations consequent to wheat ingestion in subjects without celiac disease and wheat allergy. Few studies investigated the relationship between NCWS and autoimmunity. The aim of this study is to evaluate the frequency of autoimmune diseases (ADs) and autoantibodies in patients with NCWS. Ninety-one patients (13 men and 78 women; mean age of 40.9 years) with NCWS, recruited in a single center, were included. Seventy-six healthy blood donors (HBD) and 55 patients with a diagnosis of irritable bowel syndrome (IBS) unrelated to NCWS served as controls. Autoantibodies levels were measured. Human leukocyte antigen haplotypes were determined, and duodenal histology performed in all patients carrying the DQ2/DQ8 haplotypes. Participants completed a questionnaire, and their medical records were reviewed to identify those with ADs. Twenty-three patients with NCWS (25.3%) presented with ADs; autoimmune thyroiditis (16 patients, 17.6%) was the most frequent. The frequency of ADs was higher in patients with NCWS than in HBD (P = 0.002) and in patients with IBS (P = 0.05). In the NCWS group, antinuclear antibodies tested positive in 71.4% vs HBD 19.7%, and vs patients with IBS 21.8% (P < 0.0001 for both). The frequency of extractable nuclear antigen antibody (ENA) positivity was significantly higher in patients with NCWS (21.9%) than in HBD (0%) and patients with IBS (3.6%) (P = 0.0001 and P = 0.004, respectively). Among the patients with NCWS, 9.9% tested positive for antithyroglobulin, 16.5% for antithyroid peroxidase, and 14.3% for antiparietal cell antibodies; frequencies were not statistically different from controls. The presence of ADs was related to older age at NCWS diagnosis, female sex, duodenal lymphocytosis, and eosinophil infiltration. One in 4 patients with NCWS suffered from AD, and serum antinuclear antibodies were positive in a very high percentage of cases. These data led us to consider NCWS to be associated to ADs.

Proliferating cell nuclear antigen antibody testing – Getting them all

Proliferating cell nuclear antigen antibody (PCNA) is associated with systemic lupus erythematosus (SLE) and characterises a cohort of patients at risk of renal or central nervous system involvement. The antibody has also been reported in patients with hepatitis B and C virus infection. It has a pleomorphic nuclear cell cycle dependant pattern on antinuclear antibody (ANA) testing by indirect immunofluorescence (IFA). In this laboratory PCNA has been historically reported from the IFA pattern on Hep2000 cells (Immuno Concepts, USA) and not confirmed on a secondary test. An audit of PCNA pattern reported from ANA testing and incidental characterisation by immunoblot was undertaken to determine the frequency of PCNA detected. Over 4 years, 34 PCNA results were reported. Clinical details provided included SLE, joint pain and acute hepatitis. Extractable nuclear antigen antibody characterisation by immunoblot incidentally identified a further 20 samples with PCNA not reported on ANA. ANA patterns included speckled, homogeneous and nucleolar. Clinical details in this group also included SLE and joint pain. This investigation demonstrates that IFA testing alone for PCNA may miss clinically relevant cases due to a strong dominant ANA pattern. Clinical characteristics and correlation with IFA is required to validate the immunoblot PCNA result.

Paraplegia in a Teenage Girl

CASE A 16-year-old female presented to the Emergency Department unable to walk. She reported having fallen on the stairs and sustaining a right knee injury 3 months prior. Since that time, she had increasing difficulty walking to the point that her family had obtained a wheelchair for her. While the pain from the injury subsided, her left leg became weaker, which the family attributed to the left leg having “taken the strain” due to the right-sided injury. Over the past week, she developed difficulty with urination and reduced perianal sensation on wiping. She denied back pain or pain elsewhere. She otherwise felt well with no fevers and good appetite. On review of systems, no other symptoms were reported. Her only notable medical history was severe obesity, with a weight of 108 kg. She was born in the United Kingdom to parents who originated from the Democratic Republic of Congo. She had no travel history outside of the United Kingdom. She had no known contact with infectious persons. She had been fully immunized according to the UK vaccination schedule. She lived on the third floor of an apartment block with her parents and siblings. On examination, she appeared well. She was orientated to time, place and person and was lucid in conversation. She had a temperature of 36.7°C, heart rate of 99 beats/min, respiratory rate of 22 breaths/min, blood pressure of 133/85 mm Hg and oxygen saturation of 99% in ambient air. Cardiovascular, respiratory and abdominal examinations were unremarkable. There was no jaundice, anemia, clubbing, cyanosis, edema or lymphadenopathy noted. However, she had no detectable strength in the muscle groups throughout both lower limbs and had increased tone and absent reflexes. There was a sensory level at T10, perianal anesthesia and reduced anal tone. Upper limb neurologic examination was normal. Her back was nontender and had no external signs of trauma. Laboratory studies revealed a hemoglobin of 122 g/L; white cell count of 5.69 × 109/L with differential of 43.7% neutrophils, 40.1% lymphocytes, 9.3% monocytes, 6.7% eosinophils and 0.2% basophils; and platelet count 270 × 109/L. Renal, liver and thyroid function studies were normal. She had a prothrombin time 10.3 seconds, activated partial thromboplastin time of 23 seconds, and fibrinogen of 4.90 g/L. C-reactive protein was 10.6 mg/L, and erythrocyte sedimentation rate was 24 mm/h. Angiotensin-converting enzyme was 53 U/L. Serologic testing for hepatitis B, hepatitis C, HIV and human T-lymphotropic virus were all negative, but serum IgG for varicella-zoster virus was positive. She underwent emergency magnetic resonance imaging (MRI) of the spinal cord, which demonstrated a well-circumscribed, lobulated and enhancing intramedullary mass lesion extending from the inferior aspect of T10 to the inferior aspect of T11, almost filling the vertebral canal at this level. There was associated edematous change within the spinal cord between T7 and the conus at L1. The vertebrae and vertebral disks were normal. Dexamethasone was commenced, and she was transferred to the regional neurosciences specialty center. Cerebrospinal fluid was clear and colorless, with <1 white cell per mm3, and microscopy was negative for organisms including acid-fast bacilli. CSF was also negative by polymerase chain reaction for Varicella-Zoster virus, Herpes-Zoster virus1 and Herpes-Zoster virus2, Epstein-Barr virus, cytomeganovirus, enterovirus and Mycobacterium tuberculosis complex. CSF had total IgG of 51 mg/L with albumin 231 mg/L. Oligoclonal bands were negative in both serum and CSF. Serum testing for aquaporin 4, antineuronal, antinuclear, antineutrophil cytoplasm, double-stranded DNA and extractable nuclear antigen antibodies were all negative. She underwent further MRI of the brain and spinal cord (Fig. 1), which demonstrated avid, homogeneous enhancement of the intramedullary lesion and an additional left cerebellar hemispheric lesion without any meningeal enhancement. The lesions were isointense on T1 and hypointense on weighted T2 sequences, without evidence of restricted diffusion. Subsequent biopsy of the spinal lesion led to the diagnosis.FIGURE 1.: MRI images at presentation. A: Gadolinium-enhanced T2-weighted sagittal view of spine demonstrating intramedullary enhancement; (B) coronal fluid-attenuated inversion recovery sequence of brain demonstrating left cerebellar lesion without associated enhancement.