blood and immune - della torre

IgG4-Related Disease and Castleman's Disease Overview

• IgG4-related disease and Castleman's disease are similar and can be mistaken for each other.
• IgG4-related disease: Pouchy inflammatory disease without strong inflammation signs (fever, elevated inflammatory markers).
• Castleman's disease: Resembles lymphoma/hematological condition with fever, weight loss, and constitutional symptoms.
• Both resemble Sjögren's syndrome but lack sicca syndrome (dryness).

IgG4-Related Disease

• Characterized as a fibro-inflammatory condition with fibrotic and inflamed organ masses.
• One of the leading centers for clinical management of these patients is San Raffaele hospital
• Hypertrophic pachymeningitis, or a mass of the meninges is a classic clinical example with neurological manifestations.
• IgG4-related disease is highly steroid-responsive, and corticosteroids will shrink meninges and reduce inflammation.
• PET-CT scans use radioactive glucose (18 fluorodeoxyglucose) to track metabolically active cells, and is a diagnostic tool to monitor tissue inflammation and diseases like large vessel vasculitis, IgG4-related disease or Castleman's disease
• Meningeal uptake of glucose is typical, abnormal uptake is indicated by the "little tail" and is present at the site of meningitis. Corticosteroid therapy can resolve this.
• Disease is named for characteristic increase in serum IgG4 levels and presence of IgG4+ plasma cells in affected tissues.
• Pancreatic manifestation of pancreatic IgG-4 related disease has increased serum IgG4 levels compared to other conditions in differential diagnosis, such as pancreatic cancer or other benign lesions.

IgG4-Related Disease: History and Epidemiology

• Described in 2001 after scientists linked idiopathic conditions known for decades/centuries.
• First description: Late 19th century by Austrian surgeon Mikulicz (Mikulicz's disease) describing a patient with parotid/salivary and lacrimal gland swelling.
• Prevalence: 2-3/100,000 individuals.
• Predominantly affects elderly men (three times more than women).

IgG4-Related Disease: Presentation and Pathophysiology

• Presentation can be acute/subacute, compressive effect causes symptoms:
  • Eye: Eye protrusion, orbital pain.
  • Pancreas: Choledocus occlusion, jaundice.
  • Ureters: Hydronephrosis, renal insufficiency.
• Can involve single or multiple organ systems, starting in one and evolving to others.
• Relapsing-remitting course due to unknown trigger, treatment focuses on symptomatic relief.
• Blue-collar workers at higher risk, 31% have long-standing allergy history.
• Trigger activates immune response, skewed towards IgG4 production in genetically predisposed individuals.
• Myofibroblasts activation and collagen production lead to fibrosis.
• B lymphocytes contribute directly to tissue fibrosing

IgG4 Function and Clinical Manifestations

• IgG4 are "odd antibodies" and the least common IgG subclass.
• IgG4 antibodies do not bind complement, Fc receptors, or form immune complexes.
• IgG1, IgG2, and IgG3 are inflammatory, while IgG4 are anti-inflammatory.
• IgG4 antibodies sequester antigens, preventing them from binding other IgGs.
• Fab-arm exchange: IgG4 molecules exchange structures, creating new, anti-inflammatory antibodies.
• Symptoms vary based on affected organ due to formation of a fibrotic mass.
• Systemic disease with frequent symptoms including tumor/swelling of parotid/submandibular glands, tissue around the aorta.
• Retroperitoneal fibrosis/periaortitis: Grey tissue ring around the aorta, entrapping ureters, cava vein, kidneys, and leading to tumefaction of the pancreas (autoimmune pancreatitis).

IgG4-Related Disease Phenotypes

• The association between autoimmune pancreatitis and IgG4 was described by a Japanese student.
• The common symptoms of IgG4 include tumors of the salivary glands, retroperitoneal fibrosis, and autoimmune pancreatitis.
• Four clinical phenotypes: pancreato-biliary, retroperitoneal/aortitis, head and neck limited, systemic.
  • Pancreato-biliary phenotype: Affects the biliary tract and pancreas.
  • Retroperitoneal/aortitis: Affects the arteries and mimics large vessels vasculitis.
  • Head and neck limited :Affects the head and neck
  • Systemic disease: When more organs are affected at the same time.
• Fibroinflammatory disease is driven by B and T lymphocytes, the immune system is unable to remove the antigen and the inflammatory response becomes chronic triggering a larger IgG4 response.
• Mass formations are autoantigens triggers inflammation with production of IgG4

IgG4-Related Autoimmune Pancreatitis

• Autoimmune pancreatitis causes the tissue to inflame and swell with a rim of inflammatory tissue surrounding representing the inflammatory reaction
• Radiologic findings include: Diffuse or focal pancreatic enlargement, Capsule rim surrounding the pancreas on CT and MRI, Irregular narrowing of pancreatic duct on pancreatography
• It is difficult to diferentiate from pancreatic cancer, thus a pancreatectomy can be perfomred for the suspect of cancer.
• It is usually hard for pathologists to differentiate between cancerous and IgG4 tissue.
• A tumor usually grows, metastasizes, and occludes arteries, where instead it does not happen in IgG4

IgG4-Related Sclerosing Cholangitis and Vascular Phenotype

• In half the cases of autoimmune pancreatitis comes with the involvement of the billary tract involving jaundice, weight loss, abdominal pain and can lead to inflammation and fibrosis
• Aortic involvment can be also present with the aorta surrounded in fibrotic tissue either in normal/dilated dimension, which can also be an inflammatory aneurysm. Synonyms: idiopathic retroperitoneal fibrosis or periaortic fibrosis.
• A growing fibrotic process can enlarge the kindey, thus a ureteral stent is required to allow urine out of the kidney.
• If found in the chest, fibrosing mediastinitis will be found. PET-TC scans show inflamed tissues.

Head and Neck, Lung, and Kidney Involvement

• Symptomatic of Sjogren's like enlarged lacrimal glands or orbital pseudo-tumor with tumefaction are characteristics in Sjögren's patients, Sjogren presents dryness but IgG4 does not. Sarcoidosis or castleman can also be a reason
• Exophthalmos occurs when orbital strcutrues are involved with a mass pushing downwards (asymmetic dimension of eye, may lose visual cavity, diplopia)
• Hypertrophic pachymeningitis (enlarged and thickened meninges) with different neurological symptoms (motor/sensory compressed symptoms)
• Mikulicz’s disease involves the salivary glands, the submandibular glands, the parotid glands, but no anti-Ssa, Ssb antibodies which are typical of Sjogren syndrome

Lung and Kidney Systems +Labs

• Fibrotic mainfestiatons mimic cancerous single masses, plumanary fibrosis, or thikening.
• A number of clinical manifestations are present, as hematuria, proteinuria, nephrotic syndrome, and even masses, that can be both bilateral kidney masses or unilateral kidney masses.
• Tumor testing is required for IGG4+
• A CRP test can be normal but the ESR can increase for hypergammobulenmia
• Clinical/serpgoical are options for less invasive diagnostics
• Mass can be reduced after Corti-steriod treatment
• MRIs for biopsy can be performed, but can be dangerrous ( 4/10 percent are negative)

Treatment/Features/Hystology

• Treat wiyh gluco cortizoids
• Igg4 elevation is not diectoic (because many cnditions)
• Some conditions include Perphial blood, hypergamulinemia and serum 135mgdll
• Histocial with normal pancreas ( islets)
• Fiblorts, lymphocytic

Clinical Notes on Castleman's Syndrome

• Similar to IgG4-realte diseases

Sjögren's Syndrome

• Sjögren's syndrome shares several overlapping signs with IgG4 related disorders like bilateral sialoadenitis

Key Differences between Sjögren's Syndrome, IgG4-Related Disease, and Castleman's Disease:

• Dryness (Sicca Syndrome):*
• Present in Sjögren's syndrome, absent in IgG4-related disease and Castleman's disease.
• Constitutional Symptoms:*
• Fever, weight loss, and night sweats are common in Castleman's and Sjögren's syndrome, but not in IgG4-related disease.
• Tumefaction of Salivary and Lacrimal Glands:*
• Common to all three conditions (Sjögren's syndrome, IgG4-related disease, Castleman's disease).

Castleman's Disease

• Castleman's disease was described by Benjamin Castleman
• It is defined as lymphoproliferations driven by Cytokines ,
• Diagnosised via Benign lymphadenopahty
• First discribed lymphadenopathies is mediated,
• It is a deadly Disease that leads to massive mortality
• Fegenibum known for treatment
• Treatment includes Underwent transplant, and chemotherapt

Clinical Cases Related to Castleman's

• Patients can experience Bilateal secalotitios
• Elevted ESR /HyperGlobin, Lymphadenopathty/maligment
• Pets scans are performed for adomdiastinal/ inguil etc
• Most B celles are IGG4
• Patients can be treated with Ritxiumimab

Diagonsis Types for Castlemans

• Hyslicne vascula/ plasma

Multi Center/ Triggers

• Multicentribc can be cauey (HHV8) OR LPHOMA or syndromes
• Edpidologu ( 10 percent and the dieath of death is due to organ invovmenr)

Clinical Presentaion/Biops

• Any ogran /Lymphadenpathes and lymoh nodes
• Tozllzumab can block