**8. Oral involvement and xerostomia**

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

and adipose tissue

epithelium without lumen).

when the FS in the biopsy is <1 [7, 19–23].

**7. Alternative types of salivary gland biopsies in SS**

• Lack of the measurement of the infiltrate [7]

**6. Other histopathological features of LSGB**

• Age-related features in biopsy specimens (increased fibrosis, acinar atrophy,

There are also other histopathological features in the labial glands that are associated with SS and therefore might be indicative of this disease. Lymphoepithelial lesions (LELs) are striated ducts, which are infiltrated by lymphocytes with concurrent hyperplasia of the epithelial cells. They are found both in parotid and labial

Severity of the LELs can be classified into three stages: stage 1: a partial LEL (affecting <50% of the epithelium), stage 2: developed LELS (affecting 50–100% of the epithelium), and stage 3: occluded LELs (fully circumferentially affected

Besides LELs, the salivary gland of SS patients also presents a relative decrease

The main alternative types of salivary gland biopsies in SS are parotid gland biopsy and sublingual gland biopsy. Parotid gland biopsy allows the clinician to monitor the disease progression and to assess the effect of an intervention treatment in SS. Parotid tissue can be harvested easily, repeated biopsies from the same parotid gland are possible, and the histopathologic results can be compared with other diagnostic results derived from the same gland, such as secretory function, sialographic appearance, and ultrasonography. Furthermore, parotid biopsy is better in the identification of lymphomas. The main possible complications are facial nerve damage, Frey's syndrome, and development of sialoceles and salivary fistulae. A temporary change in sensation in the skin area of the incision is also a well-documented complication after parotid biopsy. Some patients might also develop preauricular hypothesis, although this is usually temporary. Furthermore, in SS, the salivary gland tissue is replaced by fatty tissue, and the risk of harvesting fatty tissue is thereby increased if done by inexperienced physicians. Parotid biopsy is particularly recommended in pediatric patients in whom SS is suspected and who have a negative minor salivary gland biopsy result. Incisional biopsy of the parotid gland overcomes most of the disadvantages of labial biopsy. When evaluating the parotid and labial biopsy, sensitivity and specificity are comparable, estimated to be 78 and 86%, respectively. Comparative studies suggest that both procedures sublingual and parotid biopsy—retain a diagnostic potential comparable to that of lip biopsy and may be associated with lower postoperative morbidity. A comparison of sublingual gland biopsy with labial gland biopsy is better than that of labial gland biopsy, whereas the specificity of the latter is greater than that of the former. Sublingual gland biopsy is a relatively safe procedure, although the postoperative complications of sublingual salivary gland biopsy include ligaturing the Wharton duct, resulting from the placement of sutures, bleeding, and swelling in the floor of the mouth. Damage to the lingual nerve related to this biopsy technique has never

in IgA + plasma cells. Several studies showed that a relative decrease of <70% IgA + plasma cells was more sensitive and more disease specific than the FS. Both features can help assess the salivary gland biopsies for the diagnosis of SS, especially

glands, and are more representative of parotid glands than labial glands.

**62**

The rate of dry mouth in SS ranged from 41% at initial diagnosis to 84% 10 years after diagnosis. Hyposalivation or xerostomia measured by sialometry is one of the objective clinical criteria in the diagnosis of SS. According to the current classification criteria of SS, an unstimulated salivary flow rate of 0.1 ml/minute in sialometry gives a score of 1 to the weighted sum of 5 items. Dryness is also a subjective symptom of SS and is associated with many clinical implications. There are two possible sources of hyposalivation. The first possible origin is the presence of mononuclear cell aggregates around the ducts and acini of salivary glands resulting in functional and structural alterations of these glands and impairing their secretory function. In addition to the direct relationship between mononuclear cell infiltrations and secretory function, there are alternative pathways, such as induction of apoptosis of epithelial glands, alterations in aquaporin distribution, or inhibition of neurotransmission by antimuscarinic antibodies, lead to impaired glandular homeostasis. The second proposed hypothesis is the destruction of the duct and acinar cells of the salivary glands, and neural degeneration and/or the inhibition of nerve transmission. Hyposialia or decreased salivation can lead to xerostomia with clinical oral symptoms [29]. Dry mouth is associated with both objective and subjective signs and symptoms. The most common complaints related to dry mouth are presented in **Table 3**.

In SS, the gingiva and mucosa of the oral cavity are not protected by salivary mucins, leading to less lubrication of the tissues. This can cause signs such as oral mucosal inflammation, mucosal sloughing, erythematous mucosa, and traumatic ulcers. Patients may demonstrate depapillation of the tongue in advanced cases. With time, the concentration of lactoferrin, potassium and cystatin C in saliva grows, while the amylase and carbonic anhydrase concentration drops. Decreased secretion of saliva, the loss of its buffer properties, and a lower concentration of saliva proteins such as histatins, mucins, IgA, and proteins rich in proline and statherins increase the risk of opportunistic infections, mainly fungal infections by *Candida albicans*. The prevalence of *Candida albicans* is >68% in patients with SS. Oral candidiasis may be asymptomatic or may show as fissured tongue, rhomboid mid-tongue, nonspecific ulcerations, prosthetic stomatopathies, or generalized candidiasis. It most often takes the form of chronic candidiasis, and less often of pseudodiphtheritic candidiasis. Candida infections often present as atrophic or erythematous candidiasis and are associated with a burning mouth, which is described by approximately one-third of patients with SS. In SS patients,

#### **Table 3.**

A dryness of the mouth in the morning and at night

A frequent need to sip water

A lip dryness, exfoliation, fissuring

A predisposition to aphthae, ulcers, and mouth sores

A burning sensation in the mouth

A dysphagia

A dysgeusia

*The most common complaints related to dry mouth.*


#### **Table 4.**

*Symptoms of oral mucosa in the Sjögren's syndrome.*

*C. albicans*, *C. tropicalis*, *C. glabrata*, and *C. parapsilosis* are mainly isolated. Apart from oral candidiasis, a number of other changes and symptoms regarding the oral mucosa may occur (**Table 4**).

Angular cheilitis may be accompanied with fungal infection. In simple cheilitis, dominant manifestations are lip exfoliation and cracking, their proneness to bleeding, periodic swelling, and burning. The lesions are mostly limited to lip vermillion, less often labial mucosa or the facial skin around the vermillion is affected. In exfoliative cheilitis, thick brown keratin plaques are also formed. Skin redness over the lip vermillion and swelling are more often observed [29].

SS patients are predisposed to rampant caries and traumatic oral lesions. Lack of antibacterial salivary proteins results in severe tooth caries, especially on the unexposed tooth spaces. Rampant cervical caries is the most typical manifestation to SS.

### **9. Laryngological and otological manifestations of SS**

The lymphocytic infiltrations are representative for all salivary glands and have other possible consequences. Although the sicca syndrome prevails, in a clinical presentation, a bilateral parotid swelling induced by progressive lymphocyte infiltration leads both to ductal inflammation and acinar destruction in about 50% of patients. Recurrent swelling and inflammations of the parotid or submandibular glands in SS are well documented. Slow salivary flow, acinar destruction, and lymphocytic infiltrations predispose to inflammation and salivary gland enlargement. This enlargement should be distinguished from lymphomas. The most significant complication of SS is the development of lymphoproliferative malignancy, which occurs in about 5% of SS patients. Malignant lymphoma, particularly mucosaassociated lymphoid tissue (MALT) lymphoma, is relatively a frequent complication of SS with an incidence ranging between 5 and 10% and a median time from SS to lymphoma diagnosis of 7.5 years. Lymphomas accompanying SS can be confirmed by histopathological examination of salivary gland biopsy. The detection of germinal centers (GC) in salivary gland biopsy can be a very sensitive and predictive feature for lymphogenesis. Antigen-driven B cell selection normally takes place in GC within secondary lymphoid organs, but there is conclusive evidence that also ectopic GC in the salivary glands of SS patients allow affinity maturation of GC B cells with somatic Ig gene hypermaturation. Parotid gland biopsy is more recommended for diagnosis of lymphomas than labial salivary glands [7, 18–23].

Dryness of the mucosa of the upper respiratory tract is a predominant symptom and results in nasal, oropharynx, nasopharynx, laryngopharynx, vocal cord dryness, and dryness of the skin of the external auditory meatus. The main laryngological symptoms accompanying SS include the following:

**65**

*Laryngological and Dental Manifestations of Sjögren's Syndrome*

• Dry nose with congestion, crusting, and epistaxis

• Dryness, crusting, or atrophy of the nasal mucosa

• Viscid secretions on the posterior pharyngeal wall and tenacious mucus over

• Facial hypaesthesia and trigeminal nerve neuropathy, and multiple cranial

Other possible laryngological manifestations of SS are early and progressive hearing loss and symptoms related to neuropathy of the eighth cranial nerve. Approximately, a quarter of patients suffer from high-frequency hearing loss of cochlear origin, as detected by impedance audiometry or auditory brainstem procedures. The immunologic theory of sensorineural hearing loss (SNHL) in SS is based on antibody activity and cytotoxic T-cell-mediated apoptosis in the inner ear. It has been suggested that these autoantibodies induce thrombosis in the labyrinthine vessels, thereby causing damage to the inner ear, resulting in SNHL. The majority of primary SS patients exhibit hearing impairments of cochlear origin, principally at high frequencies. Sensorineural damage may be attributable to vasculitis or neuritis, or may represent an ototoxic effect of the drugs used to treat primary SS. Although there is no evidence of damage to the central auditory pathways in SS, these patients tend to have a higher prevalence of sensorineural hearing impairment compared with the general population. Idiopathic hearing loss may represent the initial manifestation of systemic vasculitis, including SS. The pathomechanisms underlying cranial neuropathy in SS have not yet been explained, except for trigeminal neuropathy due to ganglionopathy. The two possible mechanisms, vascular origin with damage to the vasa nervorum, and an immunologic cause inducing lymphocytic infiltration of the nerve have been suggested in nerve palsies related to SS. Vasculitis

• Dry wax and a "milky" appearance of the tympanic membrane

*DOI: http://dx.doi.org/10.5772/intechopen.85687*

• Soreness and/or dryness of the throat

the vocal cords

• Dysphagia

• Hoarseness

• Otalgia

• Tinnitus

• Dyspnea

• Otitis externa

• Myringitis

• A chronic dry cough

• Gastrotracheal reflux

• Sensorineural hearing loss

neuropathy [30–33]

*Laryngological and Dental Manifestations of Sjögren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.85687*


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

*C. albicans*, *C. tropicalis*, *C. glabrata*, and *C. parapsilosis* are mainly isolated. Apart from oral candidiasis, a number of other changes and symptoms regarding the oral

the lip vermillion and swelling are more often observed [29].

**9. Laryngological and otological manifestations of SS**

logical symptoms accompanying SS include the following:

Angular cheilitis may be accompanied with fungal infection. In simple cheilitis, dominant manifestations are lip exfoliation and cracking, their proneness to bleeding, periodic swelling, and burning. The lesions are mostly limited to lip vermillion, less often labial mucosa or the facial skin around the vermillion is affected. In exfoliative cheilitis, thick brown keratin plaques are also formed. Skin redness over

SS patients are predisposed to rampant caries and traumatic oral lesions. Lack of antibacterial salivary proteins results in severe tooth caries, especially on the unexposed tooth spaces. Rampant cervical caries is the most typical manifestation

The lymphocytic infiltrations are representative for all salivary glands and have

Dryness of the mucosa of the upper respiratory tract is a predominant symptom and results in nasal, oropharynx, nasopharynx, laryngopharynx, vocal cord dryness, and dryness of the skin of the external auditory meatus. The main laryngo-

other possible consequences. Although the sicca syndrome prevails, in a clinical presentation, a bilateral parotid swelling induced by progressive lymphocyte infiltration leads both to ductal inflammation and acinar destruction in about 50% of patients. Recurrent swelling and inflammations of the parotid or submandibular glands in SS are well documented. Slow salivary flow, acinar destruction, and lymphocytic infiltrations predispose to inflammation and salivary gland enlargement. This enlargement should be distinguished from lymphomas. The most significant complication of SS is the development of lymphoproliferative malignancy, which occurs in about 5% of SS patients. Malignant lymphoma, particularly mucosaassociated lymphoid tissue (MALT) lymphoma, is relatively a frequent complication of SS with an incidence ranging between 5 and 10% and a median time from SS to lymphoma diagnosis of 7.5 years. Lymphomas accompanying SS can be confirmed by histopathological examination of salivary gland biopsy. The detection of germinal centers (GC) in salivary gland biopsy can be a very sensitive and predictive feature for lymphogenesis. Antigen-driven B cell selection normally takes place in GC within secondary lymphoid organs, but there is conclusive evidence that also ectopic GC in the salivary glands of SS patients allow affinity maturation of GC B cells with somatic Ig gene hypermaturation. Parotid gland biopsy is more recommended for diagnosis of lymphomas than labial salivary glands [7, 18–23].

mucosa may occur (**Table 4**).

*Symptoms of oral mucosa in the Sjögren's syndrome.*

Candidiasis Angular cheilitis Simple cheilitis Exfoliative cheilitis Aphthae Aphthoid lesions Nonspecific ulcerations Paleness of the oral mucosa Staphylococcal infection

to SS.

**Table 4.**

**64**


Other possible laryngological manifestations of SS are early and progressive hearing loss and symptoms related to neuropathy of the eighth cranial nerve. Approximately, a quarter of patients suffer from high-frequency hearing loss of cochlear origin, as detected by impedance audiometry or auditory brainstem procedures. The immunologic theory of sensorineural hearing loss (SNHL) in SS is based on antibody activity and cytotoxic T-cell-mediated apoptosis in the inner ear. It has been suggested that these autoantibodies induce thrombosis in the labyrinthine vessels, thereby causing damage to the inner ear, resulting in SNHL. The majority of primary SS patients exhibit hearing impairments of cochlear origin, principally at high frequencies. Sensorineural damage may be attributable to vasculitis or neuritis, or may represent an ototoxic effect of the drugs used to treat primary SS. Although there is no evidence of damage to the central auditory pathways in SS, these patients tend to have a higher prevalence of sensorineural hearing impairment compared with the general population. Idiopathic hearing loss may represent the initial manifestation of systemic vasculitis, including SS. The pathomechanisms underlying cranial neuropathy in SS have not yet been explained, except for trigeminal neuropathy due to ganglionopathy. The two possible mechanisms, vascular origin with damage to the vasa nervorum, and an immunologic cause inducing lymphocytic infiltration of the nerve have been suggested in nerve palsies related to SS. Vasculitis in peripheral neuropathy and ganglionopathy in trigeminal or ataxic neuropathies have been reported as the main pathogenic etiology. The rapid and almost complete recovery from nerve palsy after therapy with corticosteroids and azathioprine suggests that lymphocytic infiltrate, rather than a vasculitic process, was the cause of cranial neuropathy in SS [33–40].
