Clinical Features

1

Introduction

The clear identification of primary Sjögren’s syndrome (pSS) as a systemic disease occurred only in the 1980s and 1990s. Indeed, in the early 1970s, the only characterized systemic manifestations were bronchitis sicca, interstitial nephritis, and the risk of developing lymphoma in the same patients. Later on, some nonspecific manifestations, including Raynaud phenomenon and arthralgias, were described, and in the early 1980s, clinical and immunopathological features of vasculitis associated with pSS were recognized as characteristic disease manifestations. Finally, several systemic manifestations, including arthritis, different patterns of esophageal dysfunction, and liver and muscular inflammatory involvement, were recognized, thus confirming the wide spectrum of disease clinical appearance.

2

The Many Facets of the Disease

pSS is a protean systemic disease and the clinical picture can vary considerably from relatively mild sicca symptoms, arthralgias, and fatigue to severe systemic symptoms. As a consequence, the heterogeneity of signs and symptoms often leads to a delay in diagnosis and the estimated disease incidence and prevalence vary significantly depending on the classification criteria applied, the study design, and the ethnicity. Interestingly, clinical appearance may vary according to several variables, including age at onset, sex, immunological profile, and clinical subsets. A significant influence of age on serological abnormalities and clinical expression of pSS has been demonstrated ( Table 2.1 ). Younger pSS onset is associated with greater immunological expression and lower prevalence of sicca symptoms in comparison with patients who are older at the onset of disease. Patients aged younger than 35–40 years, in comparison with older ones, display a higher prevalence of circulating anti-Ro/SSA, anti-La/SSB antibodies, rheumatoid factor (RF), and immunological markers associated with a more active disease, including pancytopenia, low complement levels, and hypergammaglobulinemia. On the other hand, pSS patients older than 65 years appear less likely to have RF, hypergammaglobulinemia, leukopenia, and anti-Ro/SSA or anti-La/SSB antibodies, but more likely to have a decreased unstimulated whole salivary flow rate and lung involvement. Ethnicity and demographic factors may influence age-related variability in disease manifestations and the lower autoimmune characterization of the disease in older subjects may reflect senescence of the immune system.

Gender may also influence disease immunological and clinical expression. Indeed, about 3% to 11% of pSS patients are men ( Table 2.2 ). A lesser autoimmune expression, either clinical, histological, sialographic or immunological, has been described in males. In particular, pSS in males is characterized by a lower rate of altered ocular tests and lower prevalence of some immunological features, including RF, anti-La/SSB and anti-Ro/SSA. Similarly, the prevalence of some specific extraglandular manifestations, such as Raynaud phenomenon, autoimmune thyroiditis, arthritis, cutaneous vasculitis and renal involvement, appears to be slightly lower in men.

Although some immunological markers, in particular anti-Ro/SSA, anti-La/SSB, RF and cryoglobulins, have an undeniably important diagnostic and prognostic role, a seronegative form of pSS, first described in 1996, has been reported in up to one-third of patients. The analysis of this “immunonegative” subset showed a lower incidence of extraglandular features, mainly Raynaud phenomenon and cutaneous vasculitis, in these patients. On the other hand, positivity for antinuclear antibodies, anti-Ro/SSA, anti-La/SSB, RF, or cryoglobulins is associated with a more active immunological profile with higher risk of hematological and systemic involvement. Indeed, the presence of more systemic autoantibodies may be considered a reflection of B cell hyperreactivity and a clear direct relationship has been demonstrated between the number of autoantibodies and extraglandular manifestations. The subset of patients with pSS and anti-Ro/SSA and/or La/SSB probably represents the most clinically and immunologically “active” presentation of the disease, characterized by severe systemic complications, polyclonal B cell activation profile, and higher need for corticosteroids and immunosuppressive drugs. In particular, anti-Ro/SSA positivity has been shown to be the strongest contributor for systemic extraglandular manifestations, including parotid swelling, lymphadenopathy, cutaneous vasculitis, and neurologic involvement in different SS cohorts. Key phenotypic SS features are more prevalent and disease activity is higher in anti-Ro/SSA positive subjects with respect to those who are anti-La/SSB positive alone or negative for both. RF and cryoglobulins are commonly observed in seropositive patients and contribute to higher risk of extraglandular and immunological features, including articular involvement and cutaneous vasculitis. Of interest, pSS patients displaying at least two serological markers of severe disease, including low levels of C3/C4, RF positivity, hypergammaglobulinemia, and cryoglobulins, are at a higher risk of developing both disease-related systemic manifestations, requiring immunosuppressive therapy, and non-Hodgkin lymphoma in comparison to patients with one or no serological marker. These findings confirm that an active serological profile suggestive of B cell chronic activation is associated with a higher risk of systemic complications.

Ethnicity and genetic background may also influence disease expression. As depicted in Table 2.2 , Indian and Chinese patients are younger at diagnosis by a decade as compared with European cohorts. Moreover, a smaller percentage of Chinese patients presented sicca symptoms with respect to the other cohorts of different ancestry. This could imply a difference in genetic and environmental factors contributing to the variability of disease appearance. The relevance of both innate and adaptive immune responses in the pathogenesis of the disease may also be reflected by the substantial variability of extraglandular manifestation prevalence in the different cohorts (see Table 2.2 ). For example, Raynaud phenomenon has been described in 50% of a Finland cohort and only 10% of Chinese patients. Similarly, arthritis was detected in 48% of Hungarian patients, in 14% of Swedish patients, and only 1% of cases in the Netherlands. The influence of different genetic, lifestyle, and geographical factors in association with differences in the recruitment criteria employed and in methods for assessing the single extraglandular involvement may account for this variability. Moreover, development of systemic manifestations may affect disease prognosis and patients with extraglandular involvement have a twofold to threefold higher mortality risk in comparison to the glandular group. Finally, it is relevant to consider that about half of pSS patients may develop an associated autoimmune disease, mainly autoimmune thyroid disease, and that up to 40% of patients are at risk of developing more than one concomitant autoimmune disease. This risk seems particularly increased in female patients and in subjects with circulating anti-Ro/SSA and/or anti-La/SSB antibodies.

3

Glandular Manifestations

The lymphocytic infiltration of lacrimal and salivary glands results in dry eye and dry mouth, the hallmarks of pSS. Aqueous-deficient dry eye represents the main mechanism associated with reduced tear production in pSS, leading to a typical condition of keratoconjunctivitis sicca. An evaporative dry eye, in which the evaporation of tear film is abnormally high, has been reported in SS as adjunctive mechanism. Recurrent sensation of gritty eyes; daily, persistent dry eyes; frequent need for tear substitutes; intolerance of contact lenses in association with redness, photophobia, and burning; and fluctuating blurry vision exacerbated by prolonged visual effort or a low-humidity environment represent the most common symptoms. Almost all pSS patients have a history of dry eyes for an average of 10 years before presentation and about 10% of all subjects with clinically significant dry eye have a subsequent diagnosis of pSS. Moreover, about a quarter of SS patients may experience extraglandular ocular involvement, including corneal scarring, ulcer or perforation, conjunctivitis, or conjunctival chemosis, uveitis, scleritis, optic neuropathy, or orbital inflammation. Patients with vision-threatening extraglandular ocular findings are four times more likely to have systemic disease manifestations, in particular peripheral neuropathy, vasculitis, and interstitial nephritis. Of interest, men with pSS have a sevenfold higher risk of developing vision-threatening extraglandular ocular complications, in particular corneal melt or perforation, with respect to women.

Evaluation of tear stability, by tear film breakup time, tear secretion and composition, and ocular surface represent valuable tools that can be employed in the assessment of dry eye. In particular, determination of tear secretion rate by Schirmer test differentiates aqueous-deficient dry eye from evaporative dry eye. Recently, experimental in vitro and in vivo studies identified specific molecules that have been proposed as useful biomarkers of ocular surface damage. In this setting, downregulation of PAX6, a key regulator of corneal lineage integrity, and activation of nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a protein involved in modulation of inflammation and immune response in conjunctival cytology specimens of pSS patients correlated with the extent of corneal damage and level of local inflammation.

The decrease in salivary flow in pSS patients causes xerostomia and indirect signs of mucosal dryness, including dry and cracked lips, oral mucosal sores, and tongue depapillation. Dry mouth makes talking difficult, impedes tasting and chewing properly, and causes dysphagia and dysgeusia, thus impairing quality of life of these patients. The impairment of saliva protein content, in particular of secretory immunoglobulin (Ig) A, reduces the antibacterial defense system against caries with consequent recurrent oral bacterial and fungal infections (in particular Candida albicans ), periodontal inflammation, traumatic oral lesions with angular cheilitis, high incidence of caries, and earlier tooth loss. Moreover, patients may complain of a sensation of oral burning or glossodynia, generally resulting from secondary fungal infection or SS-associated peripheral neuropathy. Swelling of salivary glands can also occur alongside with dry mouth. About 25% to 66% of pSS patients have enlarged parotid or submandibular glands and persistent salivary gland swelling has been associated with a higher risk of developing lymphoproliferative disorder.

As previously mentioned, pSS alters the protein profile and composition of saliva. Surface-enhanced laser mass spectrometry and two-dimensional gel electrophoresis have been employed in screening and profiling the proteins characterizing the saliva of these patients. An increase in the amounts of lactoferrin, β ₂ -microglobulin (B2M), lysozyme C, and cystatin, related to the inflammatory activity in the salivary gland, and a decrease in salivary amylase and carbonic anhydrase have been demonstrated in patients with pSS. Indeed, recent progress in proteomics and genomics has shown that the proteomic and genomic profile may be more sensitive and specific in diagnosing SS. In particular, three protein biomarkers (cathepsin D, a-enolase and B2M) and three mRNA biomarkers (myeloid cell nuclear differentiation antigen, guanylate-binding protein 2, and the low-affinity IIIb receptor for the Fc fragment of IgG) were all significantly increased in patients with pSS compared with both patients with systemic lupus erythematosus and healthy controls. The combination of cathepsin D, a-enolase, and B2M yielded a very high value in distinguishing pSS from healthy subjects, thus confirming the important role of salivary flow proteomic as early diagnostic and prognostic tool in pSS patients.

All exocrine glands, other than salivary and lacrimal ones, may be affected. About 70% of pSS women report reduced vaginal secretion with consequent dyspareunia and sexual dysfunction with a subsequent significant impairment on quality of life. Moreover, dry skin (xeroderma) and dry hair are commonly reported symptoms. Voice disorders and hoarseness related to dryness or thick mucus coating the vocal cords are relatively common in pSS and are more common as disease severity worsens. Finally, about 50% of pSS patients complain of a constant dry cough related to reduced or absent mucociliary clearance (xerotrachea). Patients with xerotrachea usually have difficulties in clearing thickened secretions and are thus predisposed to atelectasis, bronchiectasis, recurrent bronchitis, and bronchopneumonia.

4

Systemic Involvement

The complex T and B cell network characterizing disease pathogenesis and the importance of the dysregulation of innate and adaptive immune system involved in disease initiation and perpetuation mirror the wide spectrum of systemic disease manifestations. Indeed, in association with nonspecific symptoms and glandular manifestation, the disease clinical picture encompasses a wide spectrum of extraglandular features ( Fig. 2.1 ). Systemic manifestations are traditionally categorized in two main subsets, including a periepithelial one, which reflects the lymphocytic infiltration around epithelial tissues in parenchymal organs, and a set of manifestations related to the deposition of immune complexes in small vessels of different tissues as result of B cell hyperactivity.

5

Nonspecific Manifestations

About 70% of patients complain of nonspecific signs and symptoms, including fatigue, myalgias, low-grade fever, Raynaud phenomenon, and a widespread musculoskeletal pain that often reflects a concomitant fibromyalgic syndrome. Fibromyalgia has been reported in about 20% of pSS patients. No differences have been depicted in SS-related activity and damage and in the number of tender points between patients with pSS and concomitant fibromyalgia and patients with primary fibromyalgia. This finding suggests that fibromyalgia can contribute to fatigue and pain in pSS but does not completely account for it.

Arthritis and arthralgias represent some of the most common extraglandular manifestations in pSS patients (see Table 2.2 ). Articular manifestations are reported as the presenting manifestation in 50% of patients and in about 17% of cases, joint symptoms occur before sicca symptoms. Arthralgias involving equally small and large joints are the most common reported symptoms, in association with episodes of intermittent, symmetrical, nonerosive polyarthritis, mainly affecting the small joints, or recurrent monoarthritis or oligoarthritis in 4% to 20% of cases. Mild or moderate synovial hypertrophy has been detected by ultrasound in 15% of patients. Synovial biopsies have rarely been performed and have shown nonspecific infiltration with mononuclear cells. Of interest, pSS patients with articular manifestations have a higher risk of systemic manifestations, including renal involvement, cutaneous vasculitis, and peripheral neuropathy, and a more active immunological profile. An inflammatory articular involvement consistent with rheumatoid arthritis can develop months or years after SS diagnosis. Of note, patients with concomitant rheumatoid arthritis and SS were found to have less salivary gland enlargement, vasculitis, leukopenia, and positive antinuclear antibody titer, but more severe radiographic changes compared with patients with pSS.

6

Periepithelial Manifestations