*4.3. Stomatologic Manifestations*

Lymphocytic infiltration of SG generates exocrinopathy with hyposialia responsible for soreness, adherence of food to the mucosa, dysphagia, difficulties in speaking or eating, dental caries, tooth loss, periodontal involvement, lip dryness and nonspecific ulcerations and aphthae [206,208]. Oral candidiasis and angular cheilitis are mycotic complications related to the loss of antimicrobial action of saliva [209]. Parenchymal involvement can be complicated by recurrent parotid enlargement of infectious, lithiasic, inflammatory or lymphomatous origin [210]. SG may be the site of bilateral multicystic parotid masses and lymphoma.

#### *4.4. Musculoskeletal Manifestations*

Joint inflammatory manifestations are, after sicca syndrome, the most frequent manifestations of pSS (50% of patients) [211]. Patients may have arthralgia with inflammatory characteristics (morning stiffness > 30 min) or less frequently true symmetric polysynovitis mimicking rheumatoid arthritis (RA). Joint involvement of the pSS is generally moderate (<5 affected joints) and preferentially affects the small joints of the hands and upper limbs [211,212]. Joint involvement is conventionally non-erosive—except in case of an overlap with RA—but can be deforming (Jaccoud arthropathy) [211]. More rarely, pSS can be responsible for myositis. Finally, widespread pain is frequent—nearly 50% of pSS patients—resembling primary fibromyalgia [213,214].

#### *4.5. Neurological Manifestations*

Neurological manifestations of pSS are relatively frequent (18–45% of patients) and affect both the central and peripheral (sensitivomotor and autonomic included) nervous systems, with a higher prevalence of peripheral manifestations [215].

The peripheral manifestations are polymorphic and can be differentiated according to electromyographic examinations in mixed polyneuropathy, axon sensory polyneuropathy, sensory ataxic neuronopathy, axon sensorimotor polyneuropathy, pure sensory neuronopathy, mononeuritis multiplex or rarely chronic demyelinating polyradiculoneuropathy. The mechanisms mentioned are mainly lymphocytic infiltration of the dorsal root ganglia (for sensory ganglioneuronopathy), vasculitic lesions of the vasa nervorum and/or the presence of axon-specific autoantibodies. The cranial nerves can also be involved, essentially the trigeminal nerve by involvement of the Gasser ganglion (associated or not with a more extensive ganglionopathy) and the facial nerve (uni- or bilateral paralysis). The other cranial nerves are affected anecdotally. Finally, damage to non-myelinated fibres can be responsible of autonomic neuropathy or small-fibre neuropathy.

In the central nervous system, pSS may be responsible for encephalic or spinal manifestations, with stroke-like or Multiple Sclerosis-like damage secondary to cerebral vasculitis. Some demyelinating manifestations combining myelitis and optic neuritis are part of an associated neuromyelitis optica spectrum disorder (NMOSD), a condition linked to the presence of anti-aquaporin 4 autoantibodies. Neuro-pSS can also manifest as a recurrent aseptic lymphocytic meningitis. Rarely, the association of upper and lower motor neuron diseases resulting in an amyotrophic lateral sclerosis-like syndrome has been described during pSS.

Finally, cognitive dysfunction ("brain frog"), restless leg syndrome and psychiatric abnormalities are classically linked to pSS, but it is not clear whether these manifestations are reactive or directly linked to the pathophysiology of the disease.

#### *4.6. Pulmonary Manifestations*

The prevalence of clinically significant lung disease in pSS is 9–20% although subclinical manifestations can be found in more than 50% of patients by CT-scan or bronchoalveolar lavage findings. pSS exocrinopathy also affects the lower airways causing coughing, tracheobronchitis sicca, bronchial hyperresponsiveness (mimicking late-onset asthma), cylindrical bronchiectasis and bronchiolitis (mainly follicular bronchiolitis). This involvement of the small airway epithelium is rarely responsible for an obstructive ventilatory syndrome (11–14%) but can be complicated by recurrent pulmonary infections or atelectasis [216,217].

Nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) are the most frequent interstitial lung diseases (ILD) patterns during pSS, corresponding to 45% and 16% of cases respectively. Lymphocytic interstitial pneumonitis (LIP) arrives in 3rd position (15% of ILD cases) and can be considered as a more specific benign diffuse lymphoproliferative disorder of pSS, probably starting from the follicular bronchiolitis. It must be differentiated from pulmonary lymphoma, which is found in 2% of pSS-ILD. Other patterns such as organizing pneumonitis are less frequent (11%) or even rare such as pulmonary amyloidosis, alveolar haemorrhage, Langerhans' histiocytosis, cavitary lung disease and/or combined pulmonary fibrosis and emphysema syndrome. However, presence of multifocal cysts on CT-scan should raise clinical suspicion for pSS-ILD [211,216,217].

Pleural involvement is rare. In fact, pSS manifests by pleurisy only in less than one percent of cases [207]. Shrinking lung syndrome occurs in extremely rare cases in pSS patients [218–223].

## *4.7. Dermatological Manifestations*

Cutaneous involvement in pSS is relatively common and multiple manifestations are described such as xeroderma, eyelid dermatitis, annular erythema/subacute cutaneous lupus-like lesions and vascular purpura (caused by cutaneous vasculitis, urticarial vasculitis, cryoglobulinemia or hypergammaglobulinemic purpura of Waldenström) [211]. More rarely pSS can be responsible for cutaneous ulcer, livedo, erythema nodosum, panniculitis, amyloidosis or granuloma annulare [209].
