**5. Criteria of IgG4-RD diagnosis**

Criteria of IgG4-RD diagnosis were developed in 2012 (**Table 2**) [44]. Summing up the criteria of IgG4-RD diagnosis: one of the most important examinations in case of an appropriate clinical picture of the disease is the histopathological examination of the affected organ. It is now believed to be the key examination. In the next chapter, the principles of histopathological examination are presented, depending on the location of the pathological lesions.

In the second point of the criteria, IgG4 serum concentration was also included. It should be minimum 135 mg/dL in an affected individual. The probability of IgG4-RD diagnosis is significantly increased when this concentration is higher than 270 mg/dL [45]. However, it should be remembered that in some patients with IgG4-RD, an increase of serum IgG4 is observed. This percentage may be as high as 40% [46, 47]. IgG4 production depends mainly on the action of interleukin 6 and 10. Moreover, it was observed that in some autoimmune diseases, the concentration of IgG4 is also increased. Among others, in primary Sjӧgren syndrome, in systemic lupus erythematosus, and rheumatoid arthritis. A similar situation was also observed in 2% of patients with cancers and in healthy population [46, 47].

In IgG4-RD, no other immunologic markers observed in rheumatoid diseases are found, including antinuclear antibodies, ANCA antibodies or decreased complement components C3 and C4 [48].

In 1/3 of patients, eosinophilia in the peripheral blood is observed [18]. However, it does not correlate with the allergic symptoms [19].

In the diagnostics of IgG4-RD, imaging plays an important role, depending on lesion location, e.g., PET, magnetic resonance, computed tomography, EUS, bronchoscopy. However, the disease has no sufficiently characteristic image in any of the imaging methods, therefore these examinations are helpful in the evaluation of the affected organs and selection of the biopsy site, but they cannot be the only methods of disease diagnosis.

Another most important component of the criteria is their application only after exclusion of all other diseases that may suggest IgG4-RD disease, including cancer. It was evaluated that neoplastic lesions may occur even in 7% of patients with IgG4-RD. Development of neoplastic lesions, including lymphomas, was reported even after 5 years from diagnosis of IgG4-RD in the orbit, with affected salivary glands and cerebrospinal meninges [49, 50]. On the other hand, there are publications denying the increased risk of cancer development in IgG4-RD [51, 52].

**77**

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

An interesting fact is that most cancers observed in patients with IgG4-RD do not contain IgG4 cells [5]. At present, there are no well-designed observational studies confirming these findings. Therefore, patients with lesions in the clinical picture or patients not responding to basic treatment, should have their diagnosis verified. The diagnostics of lesions within large salivary and lacrimal glands should take the primary Sjӧgren syndrome into consideration. One of the key clinical differences is the lack of symptoms of dryness confirmed in objective examinations in patients with IgG4-RD [47, 53] and the lack of immunological markers characteris-

Taking the above into consideration, diagnostic and therapeutic procedures were developed in 2015 in patients with suspected IgG4-RD, which is presented in

New classification guidelines were presented, during the ACR meeting in Chicago in October 2018. It were developed by 79 experts from five continents and are awaiting approval by ACR and the EULAR. The guidelines based on clinical findings, bloodwork, radiologic findings and exclusion criteria for other mimickers.

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

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

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

tic for the Sjӧgren syndrome.

*Diagnostic scheme in IgG4-RD [22, 37, 54].*

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

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

**Figure 1** [22, 54].

**Figure 1.**

mentioned organs.

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

```
Figure 1.
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*Chronic Autoimmune Epithelitis - Sjogren's Syndrome and Other Autoimmune Diseases...*

1.Characteristic symptoms of organ affection with its enlargement, or abnormal function of organ/organs

• infiltration of IgG4+ cells: >10 cells IgG4+ hpf in a high-resolution microscope and quantitative ratio

and dacryoadenitis in women [42]. Patients with IgG4-usually do not present

Criteria of IgG4-RD diagnosis were developed in 2012 (**Table 2**) [44]. Summing up the criteria of IgG4-RD diagnosis: one of the most important examinations in case of an appropriate clinical picture of the disease is the histopathological examination of the affected organ. It is now believed to be the key examination. In the next chapter, the principles of histopathological examination

In the second point of the criteria, IgG4 serum concentration was also included.

In IgG4-RD, no other immunologic markers observed in rheumatoid diseases are found, including antinuclear antibodies, ANCA antibodies or decreased comple-

In 1/3 of patients, eosinophilia in the peripheral blood is observed [18].

In the diagnostics of IgG4-RD, imaging plays an important role, depending on lesion location, e.g., PET, magnetic resonance, computed tomography, EUS, bronchoscopy. However, the disease has no sufficiently characteristic image in any of the imaging methods, therefore these examinations are helpful in the evaluation of the affected organs and selection of the biopsy site, but they cannot be the only

Another most important component of the criteria is their application only after exclusion of all other diseases that may suggest IgG4-RD disease, including cancer. It was evaluated that neoplastic lesions may occur even in 7% of patients with IgG4-RD. Development of neoplastic lesions, including lymphomas, was reported even after 5 years from diagnosis of IgG4-RD in the orbit, with affected salivary glands and cerebrospinal meninges [49, 50]. On the other hand, there are publications denying the increased risk of cancer development in IgG4-RD [51, 52].

However, it does not correlate with the allergic symptoms [19].

It should be minimum 135 mg/dL in an affected individual. The probability of IgG4-RD diagnosis is significantly increased when this concentration is higher than 270 mg/dL [45]. However, it should be remembered that in some patients with IgG4-RD, an increase of serum IgG4 is observed. This percentage may be as high as 40% [46, 47]. IgG4 production depends mainly on the action of interleukin 6 and 10. Moreover, it was observed that in some autoimmune diseases, the concentration of IgG4 is also increased. Among others, in primary Sjӧgren syndrome, in systemic lupus erythematosus, and rheumatoid arthritis. A similar situation was also observed in 2% of patients with cancers and in healthy population [46, 47].

are presented, depending on the location of the pathological lesions.

general symptoms such as fever, night sweats, or weight loss [43].

• infiltration composed of lymphocytes and plasmatic cells and fibrosis

Certain diagnosis of IgG4-RD: meeting the requirements of 1, 2, 3 Probable diagnosis of IgG4-R: meeting the requirements of 1 and 3 Possible diagnosis of IgG4-RD: meeting the requirement of 1 and 2

**5. Criteria of IgG4-RD diagnosis**

2.Increased serum IgG4 concentration ≥ 135 mg/dL 3.Characteristic changes in histopathological examination:

of IgG4+/IgG > 40%

*Criteria of IgG4-RD diagnosis.*

**Table 2.**

ment components C3 and C4 [48].

methods of disease diagnosis.

**76**

*Diagnostic scheme in IgG4-RD [22, 37, 54].*

An interesting fact is that most cancers observed in patients with IgG4-RD do not contain IgG4 cells [5]. At present, there are no well-designed observational studies confirming these findings. Therefore, patients with lesions in the clinical picture or patients not responding to basic treatment, should have their diagnosis verified.

The diagnostics of lesions within large salivary and lacrimal glands should take the primary Sjӧgren syndrome into consideration. One of the key clinical differences is the lack of symptoms of dryness confirmed in objective examinations in patients with IgG4-RD [47, 53] and the lack of immunological markers characteristic for the Sjӧgren syndrome.

Taking the above into consideration, diagnostic and therapeutic procedures were developed in 2015 in patients with suspected IgG4-RD, which is presented in **Figure 1** [22, 54].

New classification guidelines were presented, during the ACR meeting in Chicago in October 2018. It were developed by 79 experts from five continents and are awaiting approval by ACR and the EULAR. The guidelines based on clinical findings, bloodwork, radiologic findings and exclusion criteria for other mimickers.
