**6. Organ location of lesions in IgG4-RD**

The lesions may occur individually or in many organs at the same time. From the point of view of rheumatologists, the most important locations include the below mentioned organs.

#### **6.1 IgG4-RD of the head and neck**

Lesions located within the head and neck belong to the most common clinical manifestation of IgG4-RD [55, 56]. They can affect large salivary glands (submandibular salivary glands, parotid glands), thyroid, lacrimal glands, orbit with oculomotor muscles, nasal sinuses, and upper airways. Mikulicz's disease is an enlargement (usually symmetrical) of lacrimal glands, parotid and submandibular glands, and sometimes sublingual glands. In the past, Mikulicz's disease was

believed to be a subtype of Sjӧgren syndrome. Today we know that these are two different disease entities with a different treatment response. Diagnostic criteria of Mikulicz's disease include: symmetric oedema of at least two pairs of lacrimal glands, parotid or submandibular glands, present for at least 3 months, and increased serum concentration, of IgG4 > 135 mg/dL, as well as a typical histopathological picture of the affected tissues.

The term Kuttner's tumor is used in case of submandibular salivary gland enlargement.

In case of lesions located in the orbit, vision disturbances, orbital pain, swelling of the eyelids caused by infiltration of oculomotor muscles and infiltration of tumor mass in the orbit may occur. Sometimes these changes may occur in tissues around the orbit as painless facial swelling. Cases of IgG4-RD were reported with infiltration and destruction of bone tissues, resulting in a saddle-shaped nose [57]. The basis for diagnosis is always a histopathological examination.

Involvement of the thyroid in IgG4-RD is possible. Recently, a lot of effort was put into this issue. First, based on case reports, it was found that Riedel thyroiditis belongs to IgG4 diseases. Some authors suggest also that the form of Hashimoto's thyroiditis with fibrosis, leading to hypothyroidism is also caused by IgG4-RD. This could be indicated by more common occurrence of hypothyroidism in patients with autoimmune pancreatitis and IgG4-RD [58–60].

#### **6.2 Location in the lungs, mediastinum and pleura**

Lesions located in the lungs may occur in the form of pseudotumors, "milk glass" lesions, lesions resembling interstitial lung disease or honeycomb lung. Less commonly, thickening of bronchovascular bundles and interlobular septa may occur. Also, involvement of the pleura and mediastinum was reported—infiltration with lymph node enlargement. In case of disease diagnosis in this location, biopsy with a thorough differential diagnosis is needed, including cancer, vasculitis [61–63].

#### **6.3 IgG4-RD in the alimentary tract**

The first organ in which IgG4-RD was reported was pancreas. Autoimmune symptoms of pancreatitis type I include jaundice, abdominal pain, pruritus, de novo diabetes and fatty diarrhea [64–67].

Lesions characteristic for IgG4-RD may be also located in other parts of the alimentary tract, e.g., gallbladder or intestines. Clinical symptoms depend on the location of lesions and organ dysfunction caused by infiltration. They may be symptomless, as in the case of IgG4-RD findings in the removed gallbladders, or present as full-blown intestinal obstruction [47]. Involvement of bile ducts is well documented in the literature as IgG4-RD sclerosing cholangitis [68].

#### **6.4 Lesions in the kidneys**

Most commonly, tubulointerstitial inflammation is found in the course of IgG4-RD (IgG4-TIN) [69]. Rarely tumor masses in the kidneys or damage to the glomeruli are observed. However, such locations of IgG4-RD may be found in the literature too [70]. Moreover, involvement of the kidneys may be divided into directly related to the location of infiltration in the parenchyma, and indirectly related to infiltration of structures of the urinary system in the course of retroperitoneal fibrosis. Recently, also a case of renal amyloidosis AA in the course of IgG4-RD was reported. It is estimated that kidney involvement occurs in about 15% patients with IgG4-RD [70]. Besides symptoms of renal insufficiency in patients

**79**

prurigo [81, 82].

*IgG4-Related Disease and the Spectrum of Mimics in Rheumatology*

with IgG4-TIN, increased serum concentration of IgG and IgG4 is observed. In 60% of patients also hypocomplementemia is observed, in 40% eosinophilia and even in 32% antinuclear antibodies [71, 72]. In the imaging examinations, lesions in the course of IgG4-RD had a form of numerous hypodense lesions [69, 73]. At present, in diagnostics of renal lesions typical for IgG4-RD, criteria proposed by Mayo Clinic or criteria of the Japanese Society of Nephrology may be used [69, 74]. Their use does not require unconditional kidney biopsy. Considering the fact that lesions in the course of IgG4-RD are most commonly located also in other organs, biopsy of

The most common histopathological form of IgG4-RD in the kidneys is membranous nephropathy (IgG4-MGN). Lesions in the glomeruli may be isolated or occur together with TIN, which is seen more often. The infiltrate observed in IgG4-MGN composed of IgG4 cells in the wall of glomerular capillaries may imitate primary membranous nephritis. Detection of antibodies against phospholipase A2 receptor (anti-PLA2R), which do not occur in IgG4-MGN, may be then helpful [70].

Lesions of IgG4-RD type usually locate in the aorta in the form of periaortitis, aortic dilatation, and aneurysm. The lesions are usually found in the abdominal aorta [9]. Inflammatory aortic aneurysm is characterized by thickening of the aortic wall, partial fibrosis of adventitia and infiltration composed of inflammatory cells [75]. Similar changes without enlargement of vessel diameter are called periaortitis [9]. The most characteristic location of inflammatory infiltrations for IgG4-RD is the adventitia (external fibrous membrane). In case of thoracic aorta involvement, separation of the aortic layers, lymphoplasmacytic aortitis and isolated aortitis are observed [76, 77]. Arterial wall thickening is relatively low compared to lesions found in the abdominal section. In some patients, aorta involvement may occur as unexpected separation of the aortic layers or sudden cardiac death; other changes in the course of the disease were rarely reported in vessels such as carotid artery, coronary arteries, pulmonary arteries, visceral vessels, mesentery vessels, iliac and vertebral arteries, brain vessels. If present, they were reported as vasculitis or

The relationship between IgG4-RD and ANCA-associated vasculitis (AAV) has not been fully explained. It is known that these diseases have a similar clinical picture (asthma symptoms, involvement of nasal sinuses, involvement of lungs and kidneys) and may proceed with increased serum IgG4 concentration and eosinophilia in the peripheral blood. Most publications were dedicated to eosinophilic

Lesions in the central nervous system are rare. If present, they are usually found in the meninges of the brain or cranial nerves. The symptoms concerning cranial nerve involvement are most commonly caused by the presence of pseudotumors

Skin lesions in the course of IgG4-RD are rarely observed and occur mainly in systemic forms. So far, the following skin lesions in the course of IgG4-RD were reported on: erythematous papules, tarsus and brown papules resembling nodular

*DOI: http://dx.doi.org/10.5772/intechopen.83368*

**6.5 Involvement of the vessels in IgG4-RD**

granulomatosis with vasculitis (EGPA) [9].

**6.6 Location of IgG4-RD in the nervous system**

and pressure on or infiltration of the nerves [80].

**6.7 Skin lesions in IgG4-RD**

other organs is acceptable.

aneurysms [78, 79].

#### *IgG4-Related Disease and the Spectrum of Mimics in Rheumatology DOI: http://dx.doi.org/10.5772/intechopen.83368*

*Chronic Autoimmune Epithelitis - Sjogren's Syndrome and Other Autoimmune Diseases...*

pathological picture of the affected tissues.

basis for diagnosis is always a histopathological examination.

autoimmune pancreatitis and IgG4-RD [58–60].

**6.3 IgG4-RD in the alimentary tract**

novo diabetes and fatty diarrhea [64–67].

**6.4 Lesions in the kidneys**

**6.2 Location in the lungs, mediastinum and pleura**

enlargement.

believed to be a subtype of Sjӧgren syndrome. Today we know that these are two different disease entities with a different treatment response. Diagnostic criteria of Mikulicz's disease include: symmetric oedema of at least two pairs of lacrimal glands, parotid or submandibular glands, present for at least 3 months, and increased serum concentration, of IgG4 > 135 mg/dL, as well as a typical histo-

The term Kuttner's tumor is used in case of submandibular salivary gland

In case of lesions located in the orbit, vision disturbances, orbital pain, swelling of the eyelids caused by infiltration of oculomotor muscles and infiltration of tumor mass in the orbit may occur. Sometimes these changes may occur in tissues around the orbit as painless facial swelling. Cases of IgG4-RD were reported with infiltration and destruction of bone tissues, resulting in a saddle-shaped nose [57]. The

Involvement of the thyroid in IgG4-RD is possible. Recently, a lot of effort was put into this issue. First, based on case reports, it was found that Riedel thyroiditis belongs to IgG4 diseases. Some authors suggest also that the form of Hashimoto's thyroiditis with fibrosis, leading to hypothyroidism is also caused by IgG4-RD. This could be indicated by more common occurrence of hypothyroidism in patients with

Lesions located in the lungs may occur in the form of pseudotumors, "milk glass" lesions, lesions resembling interstitial lung disease or honeycomb lung. Less commonly, thickening of bronchovascular bundles and interlobular septa may occur. Also, involvement of the pleura and mediastinum was reported—infiltration with lymph node enlargement. In case of disease diagnosis in this location, biopsy with a thorough differential diagnosis is needed, including cancer, vasculitis [61–63].

The first organ in which IgG4-RD was reported was pancreas. Autoimmune symptoms of pancreatitis type I include jaundice, abdominal pain, pruritus, de

Lesions characteristic for IgG4-RD may be also located in other parts of the alimentary tract, e.g., gallbladder or intestines. Clinical symptoms depend on the location of lesions and organ dysfunction caused by infiltration. They may be symptomless, as in the case of IgG4-RD findings in the removed gallbladders, or present as full-blown intestinal obstruction [47]. Involvement of bile ducts is well

Most commonly, tubulointerstitial inflammation is found in the course of IgG4-RD (IgG4-TIN) [69]. Rarely tumor masses in the kidneys or damage to the glomeruli are observed. However, such locations of IgG4-RD may be found in the literature too [70]. Moreover, involvement of the kidneys may be divided into directly related to the location of infiltration in the parenchyma, and indirectly related to infiltration of structures of the urinary system in the course of retroperitoneal fibrosis. Recently, also a case of renal amyloidosis AA in the course of IgG4-RD was reported. It is estimated that kidney involvement occurs in about 15% patients with IgG4-RD [70]. Besides symptoms of renal insufficiency in patients

documented in the literature as IgG4-RD sclerosing cholangitis [68].

**78**

with IgG4-TIN, increased serum concentration of IgG and IgG4 is observed. In 60% of patients also hypocomplementemia is observed, in 40% eosinophilia and even in 32% antinuclear antibodies [71, 72]. In the imaging examinations, lesions in the course of IgG4-RD had a form of numerous hypodense lesions [69, 73]. At present, in diagnostics of renal lesions typical for IgG4-RD, criteria proposed by Mayo Clinic or criteria of the Japanese Society of Nephrology may be used [69, 74]. Their use does not require unconditional kidney biopsy. Considering the fact that lesions in the course of IgG4-RD are most commonly located also in other organs, biopsy of other organs is acceptable.

The most common histopathological form of IgG4-RD in the kidneys is membranous nephropathy (IgG4-MGN). Lesions in the glomeruli may be isolated or occur together with TIN, which is seen more often. The infiltrate observed in IgG4-MGN composed of IgG4 cells in the wall of glomerular capillaries may imitate primary membranous nephritis. Detection of antibodies against phospholipase A2 receptor (anti-PLA2R), which do not occur in IgG4-MGN, may be then helpful [70].
