What is IgG4 related disease (IgG4 RD)?
IgG4-RD is a systemic disease characterized by tissue infiltration by IgG4-positive plasma cells, enlargement of affected organs, and elevated serum IgG4 levels. Classification criteria are being developed. Approximately, 40% of patients present with predominantly one organ involved and 60% have multiorgan involvement. Clinical findings, CT scan, MRI scan, and positron emission tomography scan can define the extent of disease. Clinical, laboratory, pathologic, and treatment characteristics include:
- • Clinical manifestations:
- • Type 1 autoimmune pancreatitis and sclerosing cholangitis: present with obstructive jaundice due to intrapancreatic bile duct strictures. Patients may have a localized pancreatic mass or diffuse pancreatic swelling (sausage pancreas). Up to 70% have diabetes mellitus (DM) and/or malabsorption. Extrapancreatic bile duct stenosis can also be seen consistent with sclerosing cholangitis.
- • Ophthalmologic disease: lacrimal gland and orbital pseudotumors can occur. Patients should be antineutrophil cytoplasmic antibody (ANCA)-negative.
- • Salivary gland disease: more than one gland involved. Submandibular enlargement more common than parotid disease. This was previously called Mikulicz disease. Antibodies against SS-A/Ro and SS-B/La are negative.
- • Kidney disease: plasma cell-rich tubulointerstitial nephritis is most common. Membranous and other glomerulopathies as well renal pelvic and cortical lesions can be seen. Hypocomplementemia is very common.
- • Pulmonary disease: mediastinal and hilar adenopathy, thickened bronchovascular bundles, and ground-glass opacities resembling Castleman disease and sarcoidosis. Biopsies do not show granulomatous inflammation or necrotizing vasculitis.
- • Periaortitis: paravertebral band-like soft tissue enlargement along the thoracic aorta or spine. Stenosis of arteries rarely seen separating it from Takayasu’s arteritis. Involvement of infrarenal aorta and its branches particularly the iliac arteries can be seen (see Chapter 27 : Large-Vessel Vasculitis: Giant Cell Arteritis, Takayasu Arteries, and Aortitis).
- • Retroperitoneal fibrosis: usually associated with periaortitis and presents with abdominal or back pain and lower extremity edema. Causes circumferential or anterolateral lesions of infrarenal and/or iliac arteries. Renal pelvic, periureteral, and plaque-like soft tissue pelvic wall lesions are also seen. Up to 20% of patients have hydronephrosis from ureteral obstruction, and some have inflammatory aortic aneurysms. Some patients have other manifestations of extraperitoneal fibrosis (e.g., orbital pseudotumor, mediastinal fibrosis; see Chapter 27 : Large-Vessel Vasculitis: Giant Cell Arteritis, Takayasu Arteries, and Aortitis).
- • Other organs: pachymeningitis, hypophysitis, Reidel’s thyroiditis, pericarditis, mastitis, prostatitis, skin disease, lymphadenopathy, as well as other organ involvement have been reported. Many patients (33%) have a notable atopic history (e.g., asthma, allergic rhinitis, atopic dermatitis). Fever is rare and should make one consider another diagnosis.
- • Laboratory:
- • Serum IgG4 is elevated in most patients, particularly in those with more extensive disease. Other diseases can cause elevations of IgG4. However, IgG4 elevations greater than five times upper limit of normal is more characteristic of IgG4-RD.
- • Other common laboratory abnormalities include polyclonal gammopathy (IgG and IgE), hypocomplementemia (50%), and elevated ESR. CRP is typically normal or only mildly elevated. Cytopenias are not seen. Mild eosinophilia can occur but should not be greater than 3000/mm 3 .
- • Histopathology: this is the gold standard for diagnosis. Any involved organ other than lymph nodes can be biopsied. Characteristic findings include marked lymphocyte and plasma cell infiltration, storiform or swirling fibrosis, and obliterative phlebitis. Eosinophils can be seen. Immunostaining shows IgG4-positive plasma cells exceeding 40% of the total IgG-positive plasma cells and more than 10 IgG4-positive plasma cells per high-power field are present in the involved tissue. Necrotizing vasculitis and granulomatous inflammation should not be seen.
- • Pathogenesis:
- • Antigenic stimulus is unknown. Patients have upregulation of Th2 cytokines (interleukin [IL]-4, IL-5, IL-13) and Treg cytokines (IL-10, TGF-β).
- • Treatment/prognosis:
- • The disease is usually slowly progressive. Symptomatic and organ-threatening disease is treated with high-dose glucocorticoids (prednisone 40–60 mg/day) with subsequent taper to 5 mg/day by 3 months. Patients typically require low-dose maintenance therapy to prevent relapses. Treatment-resistant or relapsing disease is treated with conventional immunosuppressives for their steroid-sparing effect. Rituximab is also very effective. Ureteral obstruction and aortic aneurysms requiring stenting, surgical intervention, or other invasive procedure.