Multi-organ, fibro-inflammatory condition with tumefactive lesions of unknown etiology and characteristic histopathological features.
M/C affected organs:
Salivary & lacrimal glands
Pancreas and biliary tract
Mikulicz disease (dacryoadenitis and sialadenitis) Type 1 autoimmune pancreatitis (AIP) Kuttner’s tumour (chronic sclerosing sialadenitis) Riedels’ thyroiditis Ormond’s disease (mediastinal fibrosis, retroperitoneal fibrosis) Periaortitis Idiopathic hypocomplementic tubulointerstitial nephritis Multifocal fibrosclerosis Inflammatory pseudotumor
Many organs are involved in IgG4-related disease: This figure shows diseases that have now been re-classified to be part of IgG4-related disease, including eponymous names. | Wolfson, A. R., & Hamilos, D. L. (2017). Recent advances in understanding and managing IgG4-related disease. F1000Research, 6, F1000 Faculty Rev-185. doi:10.12688/f1000research.9399.1
1961, Sarles et al. originally described IgG4-related disease in the pancreas based on a case of pancreatitis with hypergammaglobulinemia. Yoshida et al. proposed the concept of autoimmune pancreatitis (AIP) in 1995, and in 2001, Hamano et al. noted increased serum levels of IgG4 in patients with AIP and made elevated IgG4 a diagnostic marker. Kamisawa, in 2003, noted multiple extra-pancreatic lesions in patients with AIP and identified this as a systemic disease. The nomenclature was proposed at the 2011 International IgG4-related Diseases Symposium in Boston. The term IgG4-related disease (IgG-RD) was proposed to include type I AIP and other systemic manifestations. Type II AIP was considered to represent a separate histopathological entity and was not included in this characterization.
Immunoglobulin G4-related disease (IgG4-RD) and immune pathways to therapy: Naïve B cells are activated by exposure to antigens. In tertiary lymph nodes or in tertiary lymphoid tissue within an affected tissue, T follicular helper (Tfh) cells help B cells differentiate into antibody secreting cells. Interleukins (IL) 4, 10 and 21 are critical to B-cell affinity maturation, class switching and clonal expansion. At the site of disease, B cells are thought to interact with cytolytic T cells by the mutual expression of signalling lymphocytic activation molecule 7 (SLAM7). These effector T cells secrete profibrogenic cytokines that may be critical to subsequent storiform fibrosis, and cytolytic enzymes. The exact nature of the B cell to cytotoxic T cell interaction is still unclear. Therapy targeting CD20 (rituximab) leads to a reduction of plasmablasts as a consequence of killing their parent cells; plasmablasts do not express CD20. XmAb587 1 is a monoclonal antibody therapy that targets CD19 and enhances FcγRIIb-mediated inhibition—a receptor that inhibits B-cell function. A phase II trial examining the effect of XmAb5871 in IgG4-RD has completed enrolment. Elotuzumab leads to SLAM7-induced antibody directed cellular cytotoxicity in multiple myeloma. The utility of elotuzumab in IgG4-RD is currently only theoretical. Other therapies that may interfere with the pathogenic process are beyond the scope of this article, but could include therapy targeting the BAFF APRIL pathway (belimumab, atacicept); BAFF is critical for B-cell survival. | Ag, antigen; APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BCR, B-cell receptor; CXCR5, chemokine receptor type 5; MHC, major histocompatibility complex; TCR, T cell receptor. | Haldar, D., & Hirschfield, G. M. (2018). Deciphering the biology of IgG4-related disease: specific antigens and disease? Gut, 67(4), 602 LP – 605. https://doi.org/10.1136/gutjnl-2017-314861
Obliterative phlebitis Storiform fibrosis Dense lymphoplasmacytic infiltrate (IgG4 positive plasma cells)
Patients classically present with subacute, non-specific complaints, which can be general, such as weight loss, or organ-specific complaints. The classic finding is a tumefactive lesion in at least one organ, but the disease can develop over years, adding new organs one at a time, so patients may present with multi-organ disease.
Salivary & lacrimal gland involvement:
Submandibular gland swelling (51%) Parotid gland swelling (24%) Nasal congestion (21.5%) Lacrimal gland swelling (42%) Dry mouth/dry eye (12.5%)
GI & liver symptoms:
Abdominal pain (35%) Jaundice (14%) Pruritus (13.5%) Nausea ± vomiting (12%)
Lower back pain (13.5%) Dysuria (13%)
Superficial lymphadenopathy (37%) Fever (9%) Cough (13.5%)
Suggested flow chart for IgG4-RD diagnostic work up | HPF: high-power field. FNA: Fine needle aspiration. | Al-Khalili, O. M., & Erickson, A. R. (2018). IgG-4 Related Disease: An Introduction. Missouri medicine, 115(3), 253–256.