**4. Clinical manifestations**

### **4.1 Xeropthalmia**

48 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

extraglandular manifestations of SS (Jonsson et al., 2002; Skopouli et al., 2005). It is still undetermined if these antibodies play a direct pathogenic role in the glandular damage. Nonetheless, there is evidence supporting a role of anti Ro and anti La antibodies in the local autoimmune response. Indeed, autoantibodies to Ro and La have been found in saliva and infiltrating cells of salivary glands in patients with SS. Increased mRNA production of La in acinar epithelial cells and translocation of La protein, resulting in membrane localization, in the conjunctival epithelial cells have been observed in SS patients (Hammi et

Autoantibodies against fodrin, a major constituent of the cytoskeleton, have also been detected in sera from patients with SS. Abnormal location of -fodrin on the surface of apoptotic-induced cells suggests the role of -fodrin in SS through apoptotic pathways. Aberrant proteolysis of -fodrin results in its expression at the surface of apoptotic epithelial

Autoantibodies to muscarinic M3 receptors, found in the serum of SS patients, induce the inhibition of the synapse between the efferent nerves and the salivary glands, leading to

More recently, antibodies against carbonic anhydrase II, VI and XIII have been described in

Impaired function and/or architectural destruction of epithelial cells occur in salivary glands from SS patients. Epithelial cells are now considered as playing active roles in immune defenses (Manoussakis and Kapsogeorgou, 2010). Epithelial salivary glands cells, even if not proven to act as antigen-presenting cells possess all the features to do so (Manoussakis et al., 1999; Matsumura et al., 2001). Epithelial cells might act as nonprofessional antigen-presenting cells, and thereby participate in autoimmune responses leading to the development of SS (Tsunawaki et al., 2002; Xanthou et al., 2001; Dimitriou et al., 2002; Lavie et al., 2004). Proinflammatory cytokines and other factors can induce activation of surrounding epithelial cells (Abu-Helu et al., 2001). Furthermore, as a result of apoptosis and formation of exosomes, epithelial cells present intracellular autoantigens such as the Ro and La autoantigens, further contributing to the autoimmune process. Besides, following type 1 IFN stimulation and viral infection of epithelial cells, the latter releases

A pivotal role for apoptosis as a pathogenic mechanism in SS-related glandular damage has been demonstrated. Increased apoptosis of the ductal and acinar epithelia occurs in pSS patients. Upregulation of the expression of several apoptotic-related molecules has been described in lymphocytes and epithelial cells from salivary glands of patients with SS. Epithelial cell apoptosis contributes to the glandular destructive lesions through the upregulation of molecules leading to the proteolysis of exocrine autoantigens and ensuing glandular damage. Disequilibrium between pro-apoptotic signals and anti-apoptotic mechanisms might act as the basis of epithelial cell destruction of exocrine glands in pSS. Apoptotic cell death might also function in a specific fashion favoring abnormal exposure of nuclear and cytoplasmic autoantigens thereby providing mechanism of antigen presentation to autoreactive T cells. Furthermore, anti-Ro and anti-La autoantibodies can activate

cells entailing the autoimmune process (Locht et al., 2008; Willeke et al., 2007).

BAFF thereby activating B cells (Kapsogeorgou et al., 2005; Ittah et al., 2009).

decreased saliva production (Fox and Stern, 2002; Sumida et al., 2010).

relation to renal manifestations of SS (Pertovaara et al., 2011).

al., 2005; Tzioufas et al., 1999).

**3.7 Epithelial cells activation** 

**3.8 Apoptosis** 

Xerophtalmia is often less prominent than xerostomia. It is therefore necessary to follow a detailed anamnestic investigation to detect symptoms of ocular dryness. The main complaint of xeropthalmia is foreign-body sensation, but other symptoms such as grittiness, thick rope like secretions at the inner canthus, photosensitivity, burns, and sensation of having a veil before the eyes, absence of tears after irritation or emotion are all frequent features of xerophtalmia. Xerophtalmia is due to the lymphocytic infiltration of lachrymal glands leading to reduced lachrymal flow and tear composition, thereby altering corneal and conjunctival epithelia, characterizing the known condition of keratoconjunctivitis sicca (KCS). In severe disease, functional disability with visual impairment may occur (Fox, 2005).

#### **4.2 Xerostomia**

More than 90% of patients with SS complain of symptoms resulting from functional alteration of salivary glands. The symptoms range from dry mouth and lips, the need to drink more water when eating, to difficulties in the mastication process. In the early phase

Primary Sjögren's Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances 51

The spectrum of neurological disorders associated with SS is broad ranging from peripheral neuropathy to central nervous involvement. The frequency of neurological involvement in

The cardinal features of CNS involvement in SS are very much identical to that of systemic lupus erythematosus. As such, the clinical profile includes hemiparesis, cranial neuropathy and more often optic nerve neuropathy, brainstem and cerebellar disorders, movement disorders, epilepsia. Spinal cord syndromes include transverse myelitis, Brown-Sequard syndrome and progressive myelitis. Because of the occurrence of optic neuropathy and myelitis, a diagnosis of multiple sclerosis is often evoked. Furthermore, MRI imaging shows hyperintense lesions in the white matter. Neuromyelitis optica (Devic's disease) is often associated with SS and is characterized by episodes of myelitis and optic neuropathy. The clinical features of neuropsychiatric syndrome include often cognition, anxiety, mood

Peripheral neuropathy is much more frequent than CNS involvement and precedes the diagnosis of SS. Sensory neuronopathy is considered to be distinctive of SS but sensorimotor neuropathy, sensory neuropathy, autonomic neuropathy, moneuritis multiplex are amongst other features of peripheral nervous system involvement. Trigeminal neuropathy is one of the most frequent manifestations of neurological invovement in SS (Lafitte et al., 2001). In most of the cases, sensory ataxia, painful sensory neuropathies, and trigeminal neuropathy are related to sensory ganglionitis, whereas mononeuritis multiplex and multiple cranial neuropathies are more closely associated with peripheral nerve vasculitis (Segal et al., 2008).

The manifestations of gastrointestinal tract are not very specific and include oesphageal dysmotility and gastro intestinal reflux. There are no specific liver abnormalities, which can be attributed to SS, but autoimmune hepatitis and primary biliary cirrhosis can be associated

Several hematological features such as anemia, leucopenia and thrombopenia can be present. Anemia is a rare feature and when it exists, it is rarely due to inflammation but results from hemodilution due to polyclonal hypergammaglobulinemia. Leucopenia < 4000/mm3 is present in 30% of cases. In certain cases of major hypergammaglobulinemia, a hyperviscosity syndrome can be present. Typical symptoms include headaches, visual

Patients with SS have a 20 to 40-fold risk of developing non-hodgkin lymphoma (NHL) as compared to the general population. NHL has a prevalence of about 4% in SS and occurs classically following a median of 7.5 years after its initial diagnosis. The most frequent histological type of NHL is the MALT lymphoma. The histopathological features of MALT lymphoma include reactive lymphoid follicles, small plasma cells, lymphoepithelial lesions and MZ and/or monocytoid B cells. The clinical course of NHL lymphoma is indolent and the clinical characteristics include small tumor burden and good performance status. The most frequent anatomical localizations are the salivary glands but extra nodal sites can be

SS is relatively low and might precede the diagnosis of SS (Segal et al., 2008).

changes, and depression and sleep disorders (Lafitte et al., 2001).

diseases (Mavragani and Moutsopoulos, 2010; Fox, 2005).

**4.3.5 Neurological manifestations** 

**4.3.6 Gastrointestinal features** 

**4.3.7 Serological manifestations** 

**4.4 Lymphoma** 

impairement and hemorrhages (Fox, 2005).

of the disease, xerostomia is less obvious for the patients but with disease progression and severe alteration of salivary glands, xerostomia manifests as a painful syndrome with the sensation of permanent mouth burns, taste alteration, fissuring of the tongue, angular cheleitis and ulcers. Further progression of xerostomia leads to multiple complications such as teeth decay, atrophy of lingual papillae, increased incidence of mucosal infections (primarily candidiasis) loss of teeth and ultimately dentition (Fox, 2005).
