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A dermatologic riddle: How is IgG4-related ophthalmic disease parliamentary?

DII small banner By Warren R. Heymann, MD
March 22, 2017

Immunostains of infiltrate. A, Immunostain shows an infiltrate rich in IgG4+ plasma cells. The infiltrate had an IgG4+ cell count of 80 per HPF and an IgG4+/IgG+ ratio of 80%. B, IgG immunostain shown for comparison. (A and B, original magnifications: ×20.)
Image: JAAD
IgG4-related disease (IgG4-RD) is a chronic fibro-inflammatory disorder that potentially affects virtually every organ system. It characteristically affects middle-aged men, although for lesions of the head and neck, there is an equal gender distribution. Swelling of salivary and lacrimal glands, lymphadenopathy, and type 1 autoimmune pancreatitis are the most common manifestations of the disease. Up to about half of all patients are considered atopic, displaying a mild eosinophilia and/or elevated IgE. The histopathology is characterized by lymphoplasmacytic infiltration, which may lead to significant organ dysfunction (notably in the retroperitoneum, kidney, lung, thyroid, and heart, among others). IgG4-positive plasma cells, “storiform”-like fibrosis and obliterative phlebitis are noted histologically. Therapeutically, glucocorticoids alone or in combination with B-cell depletion with rituximab induces prompt clinical response to IgG4-RD (1).
According to Takayama et al: “Dermatologists may be consulted to evaluate several seemingly disparate skin problems associated with IgG4-RD, which may include prurigo-like nodules, nonspecific, rosacea-like papules and pustules, scleroderma-like skin changes, xanthogranulomas, papules and nodules mimicking angiolymphoid hyperplasia with eosinophilia, and lymphoma-like presentations with striking swelling of secretory glands and lymph nodes, especially in the head and neck region. Skin lesions have been documented most frequently on the upper trunk, neck, scalp, auricle, postauricular area, submandibular area, and over the zygomatic arch.” (2)
Although there are no widely accepted criteria to diagnose IgG4-RD, the presence of IgG4+ plasma cells are required to establish the diagnosis (with an IgG4+/IgG4- ratio > 40% and > 10% IgG4+ plasma cells per high power field); this finding, however, is not pathognomonic, as such cells may be seen in other inflammatory conditions. While an elevated serum IgG4 (> 1.35 g/L) may help confirm the diagnosis, approximately 30-50% of patients have normal serum concentrations, even in those with characteristic histologic findings. Imaging with 18 F-fluorodeoxyglucose positron emission tomography/computerized tomography (18F-FDG PET/CT) highlights the extent of disease, although it may not distinguish IgG4-RD from other causes of inflammation or malignancy (3).

It is extraordinarily difficult to make a clinical diagnosis of IgG4-RD, however, it should be considered in the context of periorbital tumors. The main clinical differential diagnoses would be thyroid orbitopathy, sarcoidosis, Sjögren syndrome, lymphoma, Rosai-Dorfman disease or periocular xanthogranulomas. Aouidad et al reported the case of a 51-year-old woman presenting with orbital “pseudotumors” (I do not understand why these are not just “tumors” — large swellings of any cause that may be benign or malignant) that histologically demonstrated eosinophilic angiocentric sclerosis related to IgG4. Unresponsive to prednisone, she improved with rituximab, followed by surgery (4). IgG4-related ophthalmic disease (IgG4-ROD), the preferred nomenclature for IgG4-RD affecting the ocular adnexa or orbit, is a common manifestation of IgG4-RD. A large IgG4-RD disease registry in North America found ophthalmic involvement in 23 % of all IgG4-RD cases. Japanese reviews of IgG4-related pancreatitis, the most thoroughly researched manifestation of IgG4-RD, have found lacrimal gland swelling in 4 to 34 % of cases. Importantly, compared to the general population, IgG4-RD patients are at 3.5 times higher risk of developing malignancies, including lung cancer, colon cancer, and lymphoma, in particular MALT lymphoma (5).

In conclusion, the concept of IgG4-related disease has vast cutaneous and systemic implications. Should the diagnosis be confirmed, evaluation by appropriate specialist(s) dictated by the patient’s presentation, and an assessment by hematology-oncology is warranted. The title of the commentary asks how IgG4-ROD is Parliamentary. I suppose you have figured this out — as a dermatologist if you see a case you are “so moved” and the “eyes have it.”

1. Vasaitis L. IgG4-related disease: A relatively new concept for clinicians. Eur J Intern Med 2016; 27: 1-9.
2. Lowe GC, et al. Cutaneous manifestations of immunoglobulin G4-related disease: What dermatologists need to know. Int J Dermatol 2015; 54: 377-382.
3. Heymann WR: Conceptual confluence: The marriage of IgG4-related disease to adult-onset asthma with periocular xanthogranulomas. Skinmed 2016; 14: 449-51.
4. Aouidad I, et al. IgG4-related disease with orbital pseudotumors treated with rituximab combined with palpebral surgery. JAMA Dermatology 2017; 355-7.
5. Wu A, et al. IgG4-related ophthalmic disease: Pooling of published cases and literature review. Curr Allergy Asthma Rep 2015; 15: 27.

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