**4.3 Systemic manifestations**

### **4.3.1 Musculoskeletal manifestations**

More than 70% of patients complain of articular manifestations. Symmetric, non-erosive, polyarthritis affecting the small joints can also be observed and precede the sicca syndrome. Myalgias are also a frequent feature, accompanied with asthenia, fatigue and muscle tenderness, reminiscent of a fibromyalgia-like syndrome (Mavragani and Moutsopoulos, 2010).

#### **4.3.2 Respiratory manifestations**

Reduced secretion from nasal epithelial cells results in nasal crusting, epistaxis and recurrent sinusitis. Tracheal dryness results in a dry non-productive cough and dyspnoea. In > 50% of SS patients, dry irritating cough was present without any radiographic abnormalities. Bronchial hyperreactivity might lead to small airways obstruction. Due to lymphocytic hyperplasia, severe airway obstruction can also occur (Parke, 2008).

Interstitial lung disease (ILD) is a classic manifestation of SS. These patients present cough, dyspnea on exertion, bilateral pulmonary infiltrates on plain radiographs and several other abnormalities on computer tomography scanner. Later stages of the disease are characterized by its evolution to fibrosis and neutrophilic alveolitis (Parambil et al., 2006).

Lymphocytic interstitial pneumonia (LIP), previously considered as a hallmark of lung involvement in SS, forms part of the spectrum of ILD. It is a consequence of bronchus associated lymphoid tissue proliferation (BALT) (Parambil et al., 2006).

Patients with SS are at increased risk of developing lymphoma, usually low grade MALT lymphoma and primary pulmonary lymphoma. These patients present few clinical symptoms contrasting with severe radiographic changes (Parke, 2008).

Pulmonary hypertension is a very rare finding in patients with SS. Only 17 cases have been documented in the literature. Prolonged vasospasm and vasculature remodeling have been assigned to contribute to the development of this pathology (Launay et al., 2007).

#### **4.3.3 Renal manifestations**

Tubular renal acidosis and glomerulonephritis are two main features of kidney involvement in SS. Distal tubular acidosis is the most frequent renal manifestation of SS occurring in up to 20% of cases. Very often, it is asymptomatic without any clinical or biological impact. Glomerulonephritis is rare in SS, and often due to cryoglobulinemia (Aasarod et al., 2000).

#### **4.3.4 Cutaneous features**

Besides the classical features of dry skin, other skin manifestations are present. Purpura is presents as petechia, which are localized in the lower limbs. Histological analysis shows leucocytoclastic vasculitis. The symptoms usually resolve with corticosteroids. Other skin manifestations include erythema nodosa, vitiligo, and digital ulcers (Kittridge et al., 2011).

#### **4.3.5 Neurological manifestations**

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

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

More than 70% of patients complain of articular manifestations. Symmetric, non-erosive, polyarthritis affecting the small joints can also be observed and precede the sicca syndrome. Myalgias are also a frequent feature, accompanied with asthenia, fatigue and muscle tenderness, reminiscent of a fibromyalgia-like syndrome (Mavragani and

Reduced secretion from nasal epithelial cells results in nasal crusting, epistaxis and recurrent sinusitis. Tracheal dryness results in a dry non-productive cough and dyspnoea. In > 50% of SS patients, dry irritating cough was present without any radiographic abnormalities. Bronchial hyperreactivity might lead to small airways obstruction. Due to

Interstitial lung disease (ILD) is a classic manifestation of SS. These patients present cough, dyspnea on exertion, bilateral pulmonary infiltrates on plain radiographs and several other abnormalities on computer tomography scanner. Later stages of the disease are characterized by its evolution to fibrosis and neutrophilic alveolitis (Parambil et al., 2006). Lymphocytic interstitial pneumonia (LIP), previously considered as a hallmark of lung involvement in SS, forms part of the spectrum of ILD. It is a consequence of bronchus

Patients with SS are at increased risk of developing lymphoma, usually low grade MALT lymphoma and primary pulmonary lymphoma. These patients present few clinical

Pulmonary hypertension is a very rare finding in patients with SS. Only 17 cases have been documented in the literature. Prolonged vasospasm and vasculature remodeling have been

Tubular renal acidosis and glomerulonephritis are two main features of kidney involvement in SS. Distal tubular acidosis is the most frequent renal manifestation of SS occurring in up to 20% of cases. Very often, it is asymptomatic without any clinical or biological impact. Glomerulonephritis is rare in SS, and often due to cryoglobulinemia (Aasarod et al., 2000).

Besides the classical features of dry skin, other skin manifestations are present. Purpura is presents as petechia, which are localized in the lower limbs. Histological analysis shows leucocytoclastic vasculitis. The symptoms usually resolve with corticosteroids. Other skin manifestations include erythema nodosa, vitiligo, and digital ulcers (Kittridge et al., 2011).

lymphocytic hyperplasia, severe airway obstruction can also occur (Parke, 2008).

associated lymphoid tissue proliferation (BALT) (Parambil et al., 2006).

symptoms contrasting with severe radiographic changes (Parke, 2008).

assigned to contribute to the development of this pathology (Launay et al., 2007).

(primarily candidiasis) loss of teeth and ultimately dentition (Fox, 2005).

**4.3 Systemic manifestations** 

Moutsopoulos, 2010).

**4.3.1 Musculoskeletal manifestations** 

**4.3.2 Respiratory manifestations** 

**4.3.3 Renal manifestations** 

**4.3.4 Cutaneous features** 

The spectrum of neurological disorders associated with SS is broad ranging from peripheral neuropathy to central nervous involvement. The frequency of neurological involvement in SS is relatively low and might precede the diagnosis of SS (Segal et al., 2008).

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

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).

#### **4.3.6 Gastrointestinal features**

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

#### **4.3.7 Serological manifestations**

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 impairement and hemorrhages (Fox, 2005).

#### **4.4 Lymphoma**

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

Primary Sjögren's Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances 53

Gene therapy consists in the introduction of new genetic material in an individual for therapeutic purposes. Several targets for gene therapy include aquaporins, inflammatory

Initial gene therapy studies, using serotype 5 adenoviral vector (Ad5), showed extremely efficient *in vivo* gene transfer to rodent salivary glands (Mastrangeli et al., 1994). Further studies using Ad5 encoding human aquaporin 1 (Ad5hAQP1), a water channel, showed the function and potential utility of this vector to restore impaired saliva flow in rats with irradiated-induced salivary hypofunction (Delporte et al., 1997). The efficacy and scaling studies of this particular gene therapy were then performed in large animal models: rhesus macaques (O'Connell et al., 1999) and miniature pigs (Li et al., 2004). A NIH clinical trial using Ad5hAQP5 has been undertaken to test the safety and efficacy in individuals with

Gene transfer therapies based on the anti-inflammatory properties of IL-10 and vasoactive intestinal peptide (VIP) have also been proposed as future treatment of SS. Indeed, administration of adenovirus vectors encoding either human IL-10 or VIP to salivary glands from NOD mice, a mouse model for SS, led to significant salivary flow improvement (Kok et

Gene transfer has also been used to treat chronic sialadenitis and modulate apoptosis in a murine model of SS: B6-gld/gld mice deficient in Fas ligand. When infected with murine cytomegalovirus, these mice presented chronic sialadenitis similar to SS. Delivery of a recombinant adenovirus vector coding for Fas ligand to the salivary glands of these mice,

As IL17A administration to mice salivary glands, using recombinant adenoviral vector, leads to SS-like disease (Nguyen et al., 2011), localized anti-IL-17 might be effective in

BAFF is a cytokine that prevents apoptosis of B-cells and thereby contributes to the hyperreactivity of B cells and their survival. Increased BAFF secretion might explain in part the partial response of rituximab in SS patients. Targeting BAFF might therefore prove to be a future therapeutical approach (Mariette, 2008). In systemic lupus erythematous, an autoimmune disease that shares similar pathogenetic features with SS, in that both diseases are characterized by an interferon signature, Belimumab, an anti-BAFF monoclonal agent, has shown beneficial effects in a randomized controlled trial (Navarra et al., 2011). Atacicept, a fusion protein inhibiting B cell stimulation, could be a promising therapeutic

Other therapeutic perspectives for SS also include the restoration of salivary glands function using bone marrow-derived cells (BMDCs) (Tran et al., 2011) and tissue engineering of salivary glands (Kagami et al., 2011). BMDCs transplantation by intravenous injection rescues salivary gland function in mice with head and neck irradiation by preventing apoptosis, increasing tissue vascularization, increasing the number of proliferating cells, and maintaining the putative salivary stem cells (Sumita et al., 2011; Lombaert et al., 2008). Furthermore, BMDCs transplantation into NOD mice treated as well with complete Freund's adjuvant (CFA), led to both qualitative and quantitative saliva restoration, and normoglycemia (Khalili et al., 2010). Tissue engineering of salivary glands utilizes cells, biodegradable scaffold, and signals to regenerate tissues. Since the pioneer work reporting

induced a significant reduction in infiltrating lymphocytes (Fleck et al., 2001).

mediators, apoptotic molecules and intracellular molecules.

irradiation-induced parotid salivary hypofunction.

al., 2003; Lodde et al., 2006).

preventing glandular dysfunction.

drug in SS (Dorner et al., 2009).

**5.5 Other therapeutic perspectives** 

**5.4 Gene therapy** 

involved, such as stomach or kidneys.The clinical and biological factors heralding imminent are low C4 levels, palpable purpura, high 2-microglobulin levels, CD4 lymphocytopenia, parotid gland swelling and persistent enlargement and hypocaptation on salivary scintigraphy, mixed monoclonal cryoglobulinemia, leg ulcers, splenomegaly and the presence of serum or urine monoclonal bands (Voulgarelis and Moutsopoulos, 2008).
