Significant CA 19-9 elevation in IgG4-related autoimmune pancreatitis - A diagnostic dilemma.

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by dense infiltration of IgG4-positive plasma cells in the affected tissue along with characteristic storiform fibrosis that can lead to the development of tumefactive lesions in any organ. CA19-9 is a marker for pancreato-biliary malignancy, however mild to moderate elevation of CA 19-9 can also be observed in IgG4-RD autoimmune pancreatitis (AIP) and sclerosing cholangitis (IgG4-SC). Therefore, it becomes difficult to differentiate between these entities. We describe the case of a 65-year-old male with history of IgG4-RD, presenting with jaundice and abdominal pain. He was found to have a pancreatic mass with significantly elevated IgG4 162 (2-96 mg/dL and CA19-9 levels 2830 (0-35 U/ml). Patient underwent ERCP and biopsy, which ruled out pancreatic cancer and cholangiocarcinoma. He was diagnosed with IgG4-RD autoimmune pancreatitis (AIP) and sclerosing cholangitis. Treatment with steroids and rituximab resulted in significant improvement in the bilirubin and a dramatic decrease in CA19-9 levels.

Regulation of DNA damage and transcriptional output in the vasculature through a cytoglobin-HMGB2 axis.

Identifying novel regulators of vascular smooth muscle cell function is necessary to further understand cardiovascular diseases. We previously identified cytoglobin, a hemoglobin homolog, with myogenic and cytoprotective roles in the vasculature. The specific mechanism of action of cytoglobin is unclear but does not seem to be related to oxygen transport or storage like hemoglobin. Herein, transcriptomic profiling of injured carotid arteries in cytoglobin global knockout mice revealed that cytoglobin deletion accelerated the loss of contractile genes and increased DNA damage. Overall, we show that cytoglobin is actively translocated into the nucleus of vascular smooth muscle cells through a redox signal driven by NOX4. We demonstrate that nuclear cytoglobin heterodimerizes with the non-histone chromatin structural protein HMGB2. Our results are consistent with a previously unknown function by which a non-erythrocytic hemoglobin inhibits DNA damage and regulates gene programs in the vasculature by modulating the genome-wide binding of HMGB2.

Cardiac Manifestations of Sjogren's Syndrome: A Review of Literature.

Sjogren's syndrome (SS) is a chronic inflammatory disorder of the exocrine glands. It is characterized by a lymphocytic infiltrate in the lacrimal and salivary glands causing keratoconjunctivitis sicca and xerostomia. Extra-glandular involvement may be present in about one-third of patients with primary Sjogren's syndrome (pSS). The most commonly affected organs are the thyroid, lungs, gastrointestinal tract, kidneys, skin, and nervous system. Cardiac manifestations of Sjogren's syndrome are rare and not well-described in the current literature. Most of the evidence is present in the form of case reports and small case series. However, recent studies have shown that patients with Sjogren's syndrome (SS) seem to have a greater overall risk of cardiovascular (CV) events. Although not conventionally considered a feature of the disease, cardiac manifestations can lead to increased morbidity and mortality in this patient population. In this review article, we study the association between cardiac diseases and primary Sjogren's syndrome.

Nuclear cytoglobin associates with HMGB2 and regulates DNA damage and genome-wide transcriptional output in the vasculature.

Identifying novel regulators of vascular smooth muscle cell function is necessary to further understand cardiovascular diseases. We previously identified cytoglobin, a hemoglobin homolog, with myogenic and cytoprotective roles in the vasculature. The specific mechanism of action of cytoglobin is unclear but does not seem to be related to oxygen transport or storage like hemoglobin. Herein, transcriptomic profiling of injured carotid arteries in cytoglobin global knockout mice revealed that cytoglobin deletion accelerated the loss of contractile genes and increased DNA damage. Overall, we show that cytoglobin is actively translocated into the nucleus of vascular smooth muscle cells through a redox signal driven by NOX4. We demonstrate that nuclear cytoglobin heterodimerizes with the non-histone chromatin structural protein HMGB2. Our results are consistent with a previously unknown function by which a non-erythrocytic hemoglobin inhibits DNA damage and regulates gene programs in the vasculature by modulating the genome-wide binding of HMGB2.

Case of idiopathic multicentric Castleman's disease: the master mimicker.

A woman in her 20s with no medical history presented with progressive abdominal distension, right-sided abdominal discomfort, fatigue and nausea. Examination showed multifocal lymphadenopathy and hepatomegaly with tense ascites. Investigations revealed a multisystem inflammatory condition characterised by elevated acute phase reactants, anaemia, thrombocytopenia, acute kidney injury, lymphocytic ascites, hypoalbuminaemia and hypergammaglobulinaemia. HIV and human herpes virus-8 tests were both negative. In the presence of elevated ANA and SS-A/Ro antibodies, the patient was suspected to be carrying a connective tissue disease, most likely systemic lupus erythematosus (SLE). Clinical and laboratory findings fulfilled the diagnostic criteria for SLE. However, lymph node biopsy showed interfollicular plasmacytosis, associated with high interleukin 6 (IL-6) and vascular endothelial growth factor titers, together hinting towards a rare diagnosis of multicentric Castleman's disease (MCD). As we investigated further, renal biopsy was consistent with thrombotic microangiopathy which has been previously reported in MCD. Furthermore, immune staining on the renal biopsy was negative for 'full-house' immunoglobulin and complement staining pattern, which is specific for lupus nephritis, helping us exclude SLE. In light of these new findings, the patient was started on anti-IL-6 therapy which provided a successful outcome.

Sjogren syndrome presenting as atrioventricular block in an adult.

A woman in her late teens with a history of Juvenile idiopathic arthritis (JIA) and ongoing sicca symptoms presented with syncope. Upon admission, she was found to be bradycardic with a second-degree atrioventricular (AV) block. After infectious, structural and metabolic aetiologies had been ruled out, she was worked up for rheumatologic causes.Our patient had elevated titres of anti-Sjogren syndrome (SS) antibodies anti-Ro antibodies and was diagnosed with AV block secondary to SS. She was treated with a permanent pacemaker. Patient was followed up in clinic where she denied further syncopal episodes and was started on secretagogues for sicca symptoms.

Scleroderma Renal Crisis Associated With Microangiopathic Hemolytic Anemia in a Patient With Seronegative Scleroderma and Monoclonal Gammopathy.

Systemic sclerosis with negative serology, particularly that complicated by scleroderma renal crisis (SRC), is rarely encountered. We describe a patient with seronegative systemic sclerosis who developed acute kidney injury, proteinuria, and hypertensive emergency following motor vehicle-related trauma and in the setting of nonsteroidal anti-inflammatory drug use. Findings on physical examination, imaging, and skin biopsy led to a clinical diagnosis of scleroderma, despite the lack of supportive laboratory data. IgG lambda paraproteinemia was detected on workup. Bone marrow biopsy showed plasmacytosis and trace lambda-restricted plasma cells consistent with monoclonal gammopathy of undetermined significance. Chemotherapy was initially started given concern for myeloma with cast nephropathy but was later stopped after a kidney biopsy revealed thrombotic microangiopathy (TMA). The SRC associated with TMA was ultimately diagnosed, though atypical hemolytic uremic syndrome (aHUS) induced perhaps by monoclonal gammopathy or hypertension was also possible. Captopril and eculizumab were initiated for SRC and aHUS, respectively. Despite therapy, renal function did not recover, and the patient required hemodialysis indefinitely. This case highlights clinical features common to both SRC and aHUS as well as points out a few ways to differentiate between them.

Rapid Resolution of Post-COVID-19 Inflammatory Syndrome in an Adult With Targeted Inhibition of Interleukin-1B.

Multisystem inflammatory syndrome (MIS) is a severe inflammatory response that occurs days to weeks following the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). Initially known in children and named MIS-C, recently several cases of MIS in adults have been reported to the Centers for Disease Control and Prevention (CDC), leading to the recognition of a new disease MIS in adults (MIS-A). The current treatment options include high-dose steroids, intravenous immunoglobulin (IVIG), and immunosuppressive therapy. However, the pharmacologic approach remains limited to case reports and pending official guidelines to treat cases with MIS-A.  We present a case of an adult patient who had a severe inflammatory state following COVID-19 infection, who was treated with IL-1 antagonist therapy with a successful outcome.

Association Between Vitamin D and Minor Salivary Gland Inflammation.

Objective There has been increasing research regarding the effects of vitamin D on autoimmune disorders. There is some evidence of a correlation between vitamin D levels and sicca symptoms. We attempted to evaluate the correlation between vitamin D levels and inflammation of the minor salivary gland (MSG). Methods Data for 214 patients who had undergone MSG biopsy were reviewed. Eighteen patients with other autoimmune/neoplastic processes were excluded. Seventy-seven of 196 patients had serum Vitamin D levels available and were selected for this retrospective study. Demographic, clinical, and immunological features, extra-glandular manifestations, autoantibodies, and clinical laboratory tests were collected and compared between patient groups with a focus score (FS) of 0 and 1 or more. Results Out of 77, 29 patients had an FS of 0 while 48 had an FS of 1 or more. Mean vitamin D levels were noted to be lower in patients with an FS of 1 when compared to patients with an FS of 1 or more. Conclusion In this study, patients with an FS of 1 were noted to have low vitamin D levels but this association was not seen at a higher FS.

Rapid and Quantitative Detection of Human Antibodies against the 2019 Novel Coronavirus SARS CoV2 and Its Variants as a Result of Vaccination and Infection.

Measuring the antibody response to 2019 SARS CoV2 is critical for diagnostic purposes, for monitoring the prevalence of infection, and for gauging the efficacy of the worldwide vaccination effort for COVID-19. In this study, a microchip-based grating-coupled fluorescent plasmonic (GC-FP) assay was used to measure antibody levels that resulted from COVID-19 infection and vaccination. In addition, we measured the relative antibody binding toward antigens from the CoV2 virus variants strains B.1.1.7 (Alpha) and B.1.351 (Beta). Antibody levels against multiple antigens within the SARS CoV2 spike protein were significantly elevated for both vaccinated and infected individuals, while those against the nucleocapsid (N) protein were only elevated for infected individuals. GC-FP was effective for monitoring the IgG-based serological response to vaccination throughout the vaccination sequence and also resolved acute (within hours) increases in antibody levels. A significant decrease in antibody binding to antigens from the B.1.351 variant, but not B.1.1.7, was observed for all vaccinated subjects when measured by GC-FP compared to the 2019 SARS CoV2 antigens. These results were corroborated by competitive enzyme-linked immunosorbent assay (ELISA). Collectively, the findings suggest that GC-FP is a viable, rapid, and accurate method for measuring both overall antibody levels to SARS CoV2 and relative antibody binding to viral variants during infection or vaccination. IMPORTANCE In this work, a novel biosensor technology was used to measure antibody levels that resulted from vaccination against COVID-19 and/or from infection with the virus. Importantly, this approach enables quantification of antibody levels, which can provide information about the timing and level of immune response. Due the multiplexed nature of this approach, antibody binding to both the original 2019 SARS CoV-2 strain and variant strains can be performed simultaneously and in a short (30-min) time frame.

Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity.

Coronavirus disease 2019 (COVID-19) is associated with a wide spectrum of disease presentation, ranging from asymptomatic infection to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity and the levels of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, including virus-neutralizing titers. A serological analysis of 536 convalescent healthcare workers reveals that SARS-CoV-2-specific and virus-neutralizing antibody levels are elevated in individuals that experience severe disease. The severity-associated increase in SARS-CoV-2-specific antibody is dominated by immunoglobulin G (IgG), with an IgG subclass ratio skewed toward elevated receptor binding domain (RBD)- and S1-specific IgG3. In addition, individuals that experience severe disease show elevated SARS-CoV-2-specific antibody binding to the inflammatory receptor FcÉ£RIIIa. Based on these correlational studies, we propose that spike-specific IgG subclass utilization may contribute to COVID-19 disease severity through potent Fc-mediated effector functions. These results may have significant implications for SARS-CoV-2 vaccine design and convalescent plasma therapy.

Transthyretin amyloidosis and herpes zoster infection: a mimic of temporal arteritis.

We describe the case of a patient who presented with symptoms of persistent headaches, left-sided facial pain and blurry vision of the left eye. The patient had recovered from a herpes zoster infection of the V1 division of the trigeminal nerve 1 month prior. Serum inflammatory markers were elevated, raising concern for temporal arteritis. Empiric high-dose prednisone was initiated. Bilateral temporal artery biopsies were performed but did not show evidence of vasculitis or multinucleated giant cells. Instead, extracellular material deposits were present within the vessel walls. Congo red staining was diagnostic for amyloidosis. Liquid chromatography and mass spectrometry identified the amyloid fibrils to be transthyretin-type (ATTR) consistent with age-related amyloidosis. Temporal artery involvement of amyloidosis is rare but when present is most often due to light chain amyloidosis. Based on our review of the literature, only a few cases of temporal artery ATTR amyloidosis have been reported.

Efficacy of anakinra for idiopathic and non-idiopathic pericarditis refractory or intolerant to conventional therapy.

BACKGROUND: Anakinra, a recombinant interleukin-1 receptor antagonist is effective in treatment of idiopathic recurrent pericarditis. However, its efficacy in non-idiopathic pericarditis (secondary to a diagnosed inflammatory condition, or other known etiology) is unclear. We evaluated the efficacy of anakinra in patients with non-idiopathic (secondary to a diagnosed inflammatory condition, or other known etiology) and idiopathic pericarditis, who were intolerant or refractory to conventional therapy (colchicine and corticosteroids). METHODS: This was a single-center study in which we performed a retrospective chart review of consecutive adult patients hospitalized with pericarditis intolerant or refractory to conventional therapy who were treated with conventional therapy and anakinra between January 2016-October 2018. The control group included age-matched hospitalized pericarditis patients treated with conventional therapy only. Symptom relief at discharge, time to symptom relief and recurrence on treatment were compared. The effect of outpatient continuation of anakinra on post-treatment recurrence risk was assessed. RESULTS: Twelve patients received anakinra for pericarditis; 22 age-matched controls were identified. Ten patients (83.3%) in the conventional therapy and anakinra group and 13 patients (54.1%) in the conventional therapy groups had non-idiopathic pericarditis. All conventional therapy and anakinra patients and 16 of 22 patients in the conventional therapy group reported symptom relief at discharge (p=0.04). Time to symptom relief was decreased in the conventional therapy and anakinra group (3.75±1.87 vs 5.63±3.28 days, p=0.08). During treatment, all conventional therapy and anakinra-treated patients continued to be symptom free, while nine of 22 conventional therapy patients (40.9%) experienced recurrence (p=0.009). Recurrence risk after treatment discontinuation was similar in the conventional therapy and anakinra group and the conventional therapy group. CONCLUSIONS: In hospitalized patients with non-idiopathic or idiopathic pericarditis refractory, or intolerant to, conventional therapy, anakinra is associated with improved symptom relief and decreased recurrence risk during treatment.

Concomitant presentation of IgG4-negative idiopathic retroperitoneal fibrosis and Addison's disease.

We describe a patient who was admitted to our medical centre with acute renal failure, hyponatraemia and hyperkalaemia. CT of the abdomen and pelvis showed a retroperitoneal mass with bilateral ureteral obstruction. Biopsy revealed fibrosis with inflammatory infiltrate, but rare IgG4-positive plasma cells. After placement of bilateral pigtail nephrostomy catheters, renal failure improved but metabolic derangements remained. Morning serum cortisol level was equivocal, but with blunted response on cosyntropin stimulation testing indicating adrenal insufficiency. Serology for 21-hydroxylase antibodies was strongly positive, supporting the diagnosis of Addison's disease. In addition to nephrostomy catheters for obstructive uropathy, idiopathic retroperitoneal fibrosis was treated with mycophenolate mofetil. Physiological doses of hydrocortisone and fludrocortisone for Addison's disease were also initiated. The patient continues to be monitored for regression of the mass. Based on review of the literature, this is the first reported case of IgG4-negative idiopathic retroperitoneal fibrosis presenting with autoimmune primary adrenal insufficiency.

Successful use of anakinra for colchicine-intolerant, corticosteroid-dependent recurrent pericarditis secondary to postcardiac injury syndrome after pacemaker placement.

A 54-year-old woman was referred to our centre for the third recurrence of colchicine-intolerant, corticosteroid dependent iatrogenic post-traumatic pericarditis after pacemaker placement 3 months prior to the first episode. The initial episode and each recurrence were associated with a pericardial effusion requiring drainage. Evaluation for pericardial infection, malignancy, autoimmune disease and pacemaker lead perforation was negative. After fourth recurrence and fifth pericardial drainage in 3 months, a trial of anakinra (interleukin-1 inhibitor), in addition to swift symptom resolution successfully prevented subsequent symptomatic and echocardiographic recurrence. Corticosteroids were tapered and eventually discontinued. At 4-month follow-up, the patient continues to be on daily anakinra 100 mg subcutaneous (SQ) daily without adverse effects.

Adult-onset Still's disease with haemorrhagic pericarditis and tamponade preceded by acute Lyme disease.

A 61-year-old Caucasian man presented with a fever of unknown origin, a transient erythematous rash on his right upper extremity and chest pressure after being treated for erythema migrans (Lyme disease). Echocardiogram demonstrated a large pericardial effusion with tamponade. He underwent pericardiostomy with tube placement. Workup for infectious and malignant etiologies was negative. Histology of the pericardium showed acute on chronic fibrinous haemorrhagic pericarditis. The patient met criteria for adult-onset Still's disease. Symptoms resolved following treatment with methylprednisolone and anakinra. We believe this is the first case of adult-onset Still's disease precipitated by acute Lyme disease.

Coeliac artery dissection as a rare manifestation of Behcet's disease.

Behcet's disease is a multisystemic vasculitis. Arterial involvement in the form of acute dissection is rare. A 42-year-old Lebanese man with Behcet's disease presented with severe abdominal pain. On exam, blood pressure was 162/104 mm Hg, and he exhibited epigastric tenderness. CT angiogram demonstrated an acute dissection of the coeliac artery trunk, common hepatic artery and proper hepatic arteries, with asymmetric thickening of the proximal left subclavian artery and circumferential thickening of the abdominal infrarenal aorta suggestive of vasculitis. Treatment included intravenous clevidipine, nitroprusside and methylprednisolone, which transitioned to oral metoprolol, amlodipine and prednisone. He responded well. Arterial dissections have been described with Behcet's. We report a coeliac artery aneurysm in association with a flare of Behcet's disease. Arterial wall inflammation combined with the sheering forces of hypertension likely predisposes to arterial dissection.