Sicca syndrome

Sicca syndrome is the most common presenting feature of pSS, with 98% of patients in the largest reported series ( n = 6110) reporting subjective dryness of the mouth or eyes, and 89% reporting both . Basal tear and saliva production are diminished or absent, although stimulated secretion is often preserved. Dry eye often leads to keratoconjunctivitis sicca (KCS), with chronic eye irritation and destruction of the corneal conjunctival epithelium. Patients presenting with KCS frequently have red eyes, itching, and grittiness, a burning or scratchy sensation under the eyelids, and photosensitivity. Those with xerostomia report difficulty in chewing and swallowing dry food, difficulty in speaking continuously, and a burning sensation in the mouth; they are at an increased risk of halitosis, oral thrush, periodontal disease, and dental caries. Physical signs include dry, erythematous oral mucosa, a lobulated or depapillated red tongue ( Fig. 1 ), gum recession with cervical tooth erosions ( Fig. 2 ), and angular cheilitis.

Depapillated red tongue in a patient with primary Sjögren’s syndrome.

Gum recession, dental caries and loss of teeth in a patient with primary Sjögren’s syndrome.

Dryness of airway mucosa can result in hoarse voice, recurrent bronchitis, and pneumonitis. Reduced vaginal secretion leads to dyspareunia and impaired sexual function , and nasal, ear, and skin dryness cause local irritation, discomfort, and itch. Loss of pancreatic function and hypochlorhydria are also observed. It is important to distinguish pSS from non-autoimmune causes of sicca syndrome, as the latter do not impart a risk of systemic complications ( Table 1 ).

Glandular enlargement

Chronic or episodic swelling of the major salivary glands is frequent, with a history of parotid involvement reported at diagnosis in 82% of patients ( n = 921) . Glandular swelling may commence unilaterally, but usually becomes bilateral ( Fig. 3 ), and enlargement of an individual gland should prompt a search for other causes . A rapidly enlarging gland may herald the emergence of malignant B-cell lymphoma, and fine-needle aspiration or biopsy of the gland should be considered. Fever, malaise, and anorexia, together with an erythematous, tender gland and expression of purulent saliva, indicate a complicating bacterial infection. Immunoglobulin 4 (IgG4)-related disease is an important differential diagnosis in patients with bilateral salivary and lacrimal glandular swelling . pSS is uncommon in children, and the presenting feature is often parotid gland enlargement, predating sicca symptoms by years .

Bilateral parotid gland enlargement in a patient with primary Sjögren’s syndrome.

Systemic manifestations

The prevalence and importance of systemic manifestations in pSS is higher than ever. In a study conducted in the United Kingdom, 152 patients with pSS were retrospectively analyzed, 71% developed systemic manifestations, and 28.3% developed malignancy. Non-Hodgkin lymphoma (NHL) developed in 10.5%, risk factors being vasculitis, parotid swelling, and lymphadenopathy . Two large cohorts of Spanish and Italian patients used the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) (see below) to assess the disease activity in each organ . As shown in Table 2 , adapted from ref. , the prevalence of severe systemic manifestations in the two cohorts was very similar. A younger age at diagnosis was associated with severe systemic pSS manifestations, as well as low C3/C4 levels and the presence of cryoglobulins.

pSS may present with systemic involvement, with or without sicca symptoms. Other autoimmune diseases (organ-specific autoimmunity, SLE, systemic sclerosis, antiphospholipid syndrome, systemic vasculitis, sarcoidosis, and IgG4-RD) and non-autoimmune processes, such as cardiovascular disease, diabetes mellitus, neurodegenerative diseases, and malignancy, should be excluded. The clinician should inquire particularly about sicca symptoms, and be alert to clues from the clinical assessment and laboratory investigations, which might indicate the diagnosis of pSS ( Table 3 ).

Constitutional symptoms

Some patients, particularly children and young adults, present with constitutional symptoms including fever, night sweats, fatigue, malaise, and weight loss , with or without sicca symptoms. A history of parotid gland swelling, together with abnormal laboratory tests (cytopenias, raised erythrocyte sedimentation rate (ESR), hypergammaglobulinemia), should alert the clinician about the possibility of pSS, and the diagnosis can be confirmed by application of classification criteria (see below).

Dryness, pain, and fatigue

Many middle-aged women with pSS present with a clinical triad comprising dryness, pain, and fatigue, which has a serious negative impact on their quality of life, and may be associated with sleep disturbance, anxiety, and depression . Autonomic symptoms are common in pSS, and autonomic dysfunction may contribute in part to the dryness and fatigue experienced in pSS .

In an Australian study involving 27 pSS patients with increased prevalence of autonomic dysfunction, an association was found between increased severity of self-reported autonomic symptoms, fatigue, objective measures of autonomic dysfunction, and reduced unstimulated salivary flow . Symptoms of autonomic dysfunction were also significantly increased in a UK cohort of 317 patients with pSS . The severity of autonomic symptoms correlated independently with the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI, a composite measure of symptoms of dryness, pain, and fatigue, see below) , and disease activity was measured using ESSDAI.

Patients with pSS have increased salivary and upper airway lining surface tension , and there is evidence that increased surface tension forces are involved in the pathophysiology of obstructive sleep apnea (OSA) . In a study of 28 Australian women with pSS, there was a high prevalence of OSA (64% vs. 28% controls) . There was no overall correlation between parameters of sleep-disordered breathing and sleepiness or fatigue scores, but continuous positive airway pressure (CPAP) treatment in a small subset, who were more severely affected by OSA, led to significant symptomatic benefits . Larger studies are required to confirm an increased incidence of OSA in pSS, which would provide a useful therapeutic target to improve the quality of life of these patients.

pSS patients who manifest predominantly with symptoms of dryness, pain, and fatigue appear to represent a subgroup of pSS with less systemic involvement and less immunological features. Segal et al. found that physical impairment was significant and pain was more severe in seronegative pSS patients, while Ter Borg et al. found that pSS patients with widespread pain had a lower prevalence of autoantibodies and systemic features. In anti-Ro/La-negative patients, a minor salivary gland biopsy showing focal lymphocytic sialadenitis (FLS) is required to confirm the diagnosis of pSS. When pSS is excluded, other potential etiologies for this symptom triad include menopause, hypothyroidism, diabetes mellitus, malignancy, depression, and fibromyalgia.

Articular

Joint involvement, including arthralgia and nonerosive inflammatory arthritis, is reported in more than 50% of patients with pSS .

Cutaneous

Patients with pSS manifest a wide spectrum of cutaneous lesions. Approximately 10% of patients with pSS have annular erythema and a polycyclic, photosensitive erythematosus rash, also known as subacute cutaneous lupus erythematosus (SCLE) . This skin eruption is in the same spectrum as neonatal cutaneous lupus erythematosus, and both are strongly associated with Ro/SSA autoantibodies. Cutaneous vasculitis is reported in 10% of patients, overwhelmingly presenting as leg purpura .

Raynaud’s phenomenon

Raynaud’s phenomenon has a prevalence of 10–37% in pSS patients. Its clinical course is milder than in systemic sclerosis, which can mimic pSS.

Pulmonary

Pulmonary involvement in pSS has recently been reviewed by Stojen et al. Subclinical abnormalities of pulmonary function, bronchoalveolar lavage, and computed tomography tests are found in approximately 75% of patients. Dryness of the airways with inspissation of secretions leads to a dry cough in 50% of patients, and rhinosinusitis in 30%. The other features listed in Table 3 are less frequent.

Nervous system

Peripheral neuropathy has been reported in up to 64% of patients with pSS , and includes axonal polyneuropathy, mononeuritis multiplex, pure sensory neuropathy, and small-fiber neuropathy (SFN). Ganglionopathy or pure sensory neuronopathy is recognized as a characteristic neurologic complication of pSS, caused by damage to the sensory neurons of the dorsal root and Gasserian ganglia. Sene et al. reported the largest series of pSS patients affected by SFN, where 32 (80%) of 40 patients with SFN had previously undiagnosed pSS. Because of a relatively low frequency of Ro/La antibodies in this pSS subgroup (42% and 17%, respectively, reported by Sene et al.), clinical suspicion and salivary gland biopsy are important for diagnosis.

Cerebral white matter lesions on magnetic resonance (MR) imaging are frequently seen in pSS. A recent study found that these lesions are overwhelmingly associated with concomitant cardiovascular risk factors, although isolated cases of multiple sclerosis (MS)-like disease have been reported . Several studies have found pSS to be overrepresented in patients with neuromyelitis optica (NMO) spectrum disorders .

Renal

Renal involvement in pSS has been recently reviewed by Evans et al. Tubulointerstitial nephritis associated with type I/distal renal tubular acidosis (RTA) is an early manifestation of pSS, which is often unrecognized. It mainly presents with hypokalemic weakness (70%), and less commonly with renal colic, nephrocalcinosis, osteomalacia, and more rarely, diabetes insipidus. In contrast to tubular involvement, pSS-related glomerulonephritis (GN) is less common, and in most cases linked to noninfective cryoglobulinemic vasculitis.

Lower urinary tract

Walker et al. reported a high prevalence of severe lower urinary tract symptoms, predominantly urinary urgency, in 76 Australian women with pSS (61% vs. 40% controls) .

Autoimmune cytopenias

One-third of patients with pSS have cytopenias in the laboratory workup . Many patients with autoimmune cytopenias and positive ANA are misdiagnosed with SLE. Most cytopenias in pSS are mild and asymptomatic .

Neonatal lupus

The identification of neonatal lupus, presenting either as a transient rash, cytopenia, mild hepatic derangement, or congenital heart block (CHB), may be the first indication of pSS in the mother. In asymptomatic pregnant women, the diagnosis of fetal CHB in a structurally normal heart, particularly during weeks 16–24 of gestation, should immediately trigger an evaluation of the maternal sera for Ro/La antibodies. In a recent systematic review, 113 (13%) of 856 mothers of CHB-affected neonates had pSS . However, according to data from the US Registry, the probability of an asymptomatic mother developing probable/definite pSS during follow-up is up to 30% . In the French Registry of autoimmune CHB, pSS was also the most frequent systemic autoimmune disease, diagnosed in 124 affected mothers followed up for a mean of 5.6 years after CHB diagnosis (27% were finally diagnosed with pSS) . These data suggest that in approximately one-third of mothers who had babies with CHB, a positive immunological result may lead to an early diagnosis of pSS.

Non-Hodgkin lymphoma

pSS carries a substantially increased risk for the development of NHL. A meta-analysis of 11 studies estimated a pooled RR of 13.76 (95% CI 8.53–18.99) . A history of SS is the most important predictor of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LPL/WM), a rare NHL subtype (OR = 14.0, 95% CI 3.60–54.6) .

Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common lymphoma in pSS patients. Lymphoplasmacytoid lymphomas, also increased in pSS, are probably marginal zone lymphomas (MZL) with plasma cell differentiation. Salivary glands (parotid and submandibular) are the most frequent localization of MALT lymphomas, which usually present as parotid enlargement. Other mucosal sites can be affected, including orbits, nasopharynx, stomach, thyroid, and lung. NHL subtypes and their treatment in pSS were reviewed by Nocturne and Mariette .

While NHL-complicating pSS may often follow an indolent course, low-grade lymphomas might transform to high-grade lymphoma, mainly of the diffuse large B-cell lymphoma (DLBCL) type. There is an increase in NHL specific mortality (SMR 3.25, 95% CI 1.32–6.76) , and prognosis may differ according to NHL subtype . Further, ESSDAI scores at NHL diagnosis may be a useful prognostic indicator .

A number of studies have addressed clinical, serological, and genetic predictors for NHL risk. A review of these studies identified lymphadenopathy, parotid enlargement, palpable purpura, low C4 serum levels, and cryoglobulins as the most consistent NHL/lymphoproliferative disease predictors. Some studies identified splenomegaly, low C3 serum levels, lymphopenia, and neutropenia as significant prognostic factors. The detection of germinal center (GC)-like lesions in salivary biopsies may also be highly predictive of non-Hodgkin lymphoma . Genetic predictors of NHL in pSS include TNFAIP3 , BAFF , and possibly HLA DR3 .

Disease activity and B-cell hyperreactivity may play a key role in NHL-associated malignant transformation in pSS. There is no validated algorithm for the quantification of NHL risk, and no guidelines for the follow-up and management of at-risk patients. Available evidence indicates that pSS patients may have an increased risk for multiple myeloma and thyroid cancer , suggesting that these cancers could be included in surveillance monitoring.

Sicca syndrome

Sicca syndrome is the most common presenting feature of pSS, with 98% of patients in the largest reported series ( n = 6110) reporting subjective dryness of the mouth or eyes, and 89% reporting both . Basal tear and saliva production are diminished or absent, although stimulated secretion is often preserved. Dry eye often leads to keratoconjunctivitis sicca (KCS), with chronic eye irritation and destruction of the corneal conjunctival epithelium. Patients presenting with KCS frequently have red eyes, itching, and grittiness, a burning or scratchy sensation under the eyelids, and photosensitivity. Those with xerostomia report difficulty in chewing and swallowing dry food, difficulty in speaking continuously, and a burning sensation in the mouth; they are at an increased risk of halitosis, oral thrush, periodontal disease, and dental caries. Physical signs include dry, erythematous oral mucosa, a lobulated or depapillated red tongue ( Fig. 1 ), gum recession with cervical tooth erosions ( Fig. 2 ), and angular cheilitis.

Depapillated red tongue in a patient with primary Sjögren’s syndrome.

Gum recession, dental caries and loss of teeth in a patient with primary Sjögren’s syndrome.

Dryness of airway mucosa can result in hoarse voice, recurrent bronchitis, and pneumonitis. Reduced vaginal secretion leads to dyspareunia and impaired sexual function , and nasal, ear, and skin dryness cause local irritation, discomfort, and itch. Loss of pancreatic function and hypochlorhydria are also observed. It is important to distinguish pSS from non-autoimmune causes of sicca syndrome, as the latter do not impart a risk of systemic complications ( Table 1 ).

Glandular enlargement

Chronic or episodic swelling of the major salivary glands is frequent, with a history of parotid involvement reported at diagnosis in 82% of patients ( n = 921) . Glandular swelling may commence unilaterally, but usually becomes bilateral ( Fig. 3 ), and enlargement of an individual gland should prompt a search for other causes . A rapidly enlarging gland may herald the emergence of malignant B-cell lymphoma, and fine-needle aspiration or biopsy of the gland should be considered. Fever, malaise, and anorexia, together with an erythematous, tender gland and expression of purulent saliva, indicate a complicating bacterial infection. Immunoglobulin 4 (IgG4)-related disease is an important differential diagnosis in patients with bilateral salivary and lacrimal glandular swelling . pSS is uncommon in children, and the presenting feature is often parotid gland enlargement, predating sicca symptoms by years .

Bilateral parotid gland enlargement in a patient with primary Sjögren’s syndrome.

Systemic manifestations

The prevalence and importance of systemic manifestations in pSS is higher than ever. In a study conducted in the United Kingdom, 152 patients with pSS were retrospectively analyzed, 71% developed systemic manifestations, and 28.3% developed malignancy. Non-Hodgkin lymphoma (NHL) developed in 10.5%, risk factors being vasculitis, parotid swelling, and lymphadenopathy . Two large cohorts of Spanish and Italian patients used the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) (see below) to assess the disease activity in each organ . As shown in Table 2 , adapted from ref. , the prevalence of severe systemic manifestations in the two cohorts was very similar. A younger age at diagnosis was associated with severe systemic pSS manifestations, as well as low C3/C4 levels and the presence of cryoglobulins.

pSS may present with systemic involvement, with or without sicca symptoms. Other autoimmune diseases (organ-specific autoimmunity, SLE, systemic sclerosis, antiphospholipid syndrome, systemic vasculitis, sarcoidosis, and IgG4-RD) and non-autoimmune processes, such as cardiovascular disease, diabetes mellitus, neurodegenerative diseases, and malignancy, should be excluded. The clinician should inquire particularly about sicca symptoms, and be alert to clues from the clinical assessment and laboratory investigations, which might indicate the diagnosis of pSS ( Table 3 ).

Constitutional symptoms

Some patients, particularly children and young adults, present with constitutional symptoms including fever, night sweats, fatigue, malaise, and weight loss , with or without sicca symptoms. A history of parotid gland swelling, together with abnormal laboratory tests (cytopenias, raised erythrocyte sedimentation rate (ESR), hypergammaglobulinemia), should alert the clinician about the possibility of pSS, and the diagnosis can be confirmed by application of classification criteria (see below).

Dryness, pain, and fatigue

Many middle-aged women with pSS present with a clinical triad comprising dryness, pain, and fatigue, which has a serious negative impact on their quality of life, and may be associated with sleep disturbance, anxiety, and depression . Autonomic symptoms are common in pSS, and autonomic dysfunction may contribute in part to the dryness and fatigue experienced in pSS .

In an Australian study involving 27 pSS patients with increased prevalence of autonomic dysfunction, an association was found between increased severity of self-reported autonomic symptoms, fatigue, objective measures of autonomic dysfunction, and reduced unstimulated salivary flow . Symptoms of autonomic dysfunction were also significantly increased in a UK cohort of 317 patients with pSS . The severity of autonomic symptoms correlated independently with the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI, a composite measure of symptoms of dryness, pain, and fatigue, see below) , and disease activity was measured using ESSDAI.

Patients with pSS have increased salivary and upper airway lining surface tension , and there is evidence that increased surface tension forces are involved in the pathophysiology of obstructive sleep apnea (OSA) . In a study of 28 Australian women with pSS, there was a high prevalence of OSA (64% vs. 28% controls) . There was no overall correlation between parameters of sleep-disordered breathing and sleepiness or fatigue scores, but continuous positive airway pressure (CPAP) treatment in a small subset, who were more severely affected by OSA, led to significant symptomatic benefits . Larger studies are required to confirm an increased incidence of OSA in pSS, which would provide a useful therapeutic target to improve the quality of life of these patients.

pSS patients who manifest predominantly with symptoms of dryness, pain, and fatigue appear to represent a subgroup of pSS with less systemic involvement and less immunological features. Segal et al. found that physical impairment was significant and pain was more severe in seronegative pSS patients, while Ter Borg et al. found that pSS patients with widespread pain had a lower prevalence of autoantibodies and systemic features. In anti-Ro/La-negative patients, a minor salivary gland biopsy showing focal lymphocytic sialadenitis (FLS) is required to confirm the diagnosis of pSS. When pSS is excluded, other potential etiologies for this symptom triad include menopause, hypothyroidism, diabetes mellitus, malignancy, depression, and fibromyalgia.

Articular

Joint involvement, including arthralgia and nonerosive inflammatory arthritis, is reported in more than 50% of patients with pSS .

Cutaneous

Patients with pSS manifest a wide spectrum of cutaneous lesions. Approximately 10% of patients with pSS have annular erythema and a polycyclic, photosensitive erythematosus rash, also known as subacute cutaneous lupus erythematosus (SCLE) . This skin eruption is in the same spectrum as neonatal cutaneous lupus erythematosus, and both are strongly associated with Ro/SSA autoantibodies. Cutaneous vasculitis is reported in 10% of patients, overwhelmingly presenting as leg purpura .

Raynaud’s phenomenon

Raynaud’s phenomenon has a prevalence of 10–37% in pSS patients. Its clinical course is milder than in systemic sclerosis, which can mimic pSS.

Pulmonary

Pulmonary involvement in pSS has recently been reviewed by Stojen et al. Subclinical abnormalities of pulmonary function, bronchoalveolar lavage, and computed tomography tests are found in approximately 75% of patients. Dryness of the airways with inspissation of secretions leads to a dry cough in 50% of patients, and rhinosinusitis in 30%. The other features listed in Table 3 are less frequent.

Nervous system

Peripheral neuropathy has been reported in up to 64% of patients with pSS , and includes axonal polyneuropathy, mononeuritis multiplex, pure sensory neuropathy, and small-fiber neuropathy (SFN). Ganglionopathy or pure sensory neuronopathy is recognized as a characteristic neurologic complication of pSS, caused by damage to the sensory neurons of the dorsal root and Gasserian ganglia. Sene et al. reported the largest series of pSS patients affected by SFN, where 32 (80%) of 40 patients with SFN had previously undiagnosed pSS. Because of a relatively low frequency of Ro/La antibodies in this pSS subgroup (42% and 17%, respectively, reported by Sene et al.), clinical suspicion and salivary gland biopsy are important for diagnosis.

Cerebral white matter lesions on magnetic resonance (MR) imaging are frequently seen in pSS. A recent study found that these lesions are overwhelmingly associated with concomitant cardiovascular risk factors, although isolated cases of multiple sclerosis (MS)-like disease have been reported . Several studies have found pSS to be overrepresented in patients with neuromyelitis optica (NMO) spectrum disorders .

Renal

Renal involvement in pSS has been recently reviewed by Evans et al. Tubulointerstitial nephritis associated with type I/distal renal tubular acidosis (RTA) is an early manifestation of pSS, which is often unrecognized. It mainly presents with hypokalemic weakness (70%), and less commonly with renal colic, nephrocalcinosis, osteomalacia, and more rarely, diabetes insipidus. In contrast to tubular involvement, pSS-related glomerulonephritis (GN) is less common, and in most cases linked to noninfective cryoglobulinemic vasculitis.

Lower urinary tract

Walker et al. reported a high prevalence of severe lower urinary tract symptoms, predominantly urinary urgency, in 76 Australian women with pSS (61% vs. 40% controls) .

Autoimmune cytopenias

One-third of patients with pSS have cytopenias in the laboratory workup . Many patients with autoimmune cytopenias and positive ANA are misdiagnosed with SLE. Most cytopenias in pSS are mild and asymptomatic .

Neonatal lupus

The identification of neonatal lupus, presenting either as a transient rash, cytopenia, mild hepatic derangement, or congenital heart block (CHB), may be the first indication of pSS in the mother. In asymptomatic pregnant women, the diagnosis of fetal CHB in a structurally normal heart, particularly during weeks 16–24 of gestation, should immediately trigger an evaluation of the maternal sera for Ro/La antibodies. In a recent systematic review, 113 (13%) of 856 mothers of CHB-affected neonates had pSS . However, according to data from the US Registry, the probability of an asymptomatic mother developing probable/definite pSS during follow-up is up to 30% . In the French Registry of autoimmune CHB, pSS was also the most frequent systemic autoimmune disease, diagnosed in 124 affected mothers followed up for a mean of 5.6 years after CHB diagnosis (27% were finally diagnosed with pSS) . These data suggest that in approximately one-third of mothers who had babies with CHB, a positive immunological result may lead to an early diagnosis of pSS.

Non-Hodgkin lymphoma

pSS carries a substantially increased risk for the development of NHL. A meta-analysis of 11 studies estimated a pooled RR of 13.76 (95% CI 8.53–18.99) . A history of SS is the most important predictor of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LPL/WM), a rare NHL subtype (OR = 14.0, 95% CI 3.60–54.6) .

Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common lymphoma in pSS patients. Lymphoplasmacytoid lymphomas, also increased in pSS, are probably marginal zone lymphomas (MZL) with plasma cell differentiation. Salivary glands (parotid and submandibular) are the most frequent localization of MALT lymphomas, which usually present as parotid enlargement. Other mucosal sites can be affected, including orbits, nasopharynx, stomach, thyroid, and lung. NHL subtypes and their treatment in pSS were reviewed by Nocturne and Mariette .

While NHL-complicating pSS may often follow an indolent course, low-grade lymphomas might transform to high-grade lymphoma, mainly of the diffuse large B-cell lymphoma (DLBCL) type. There is an increase in NHL specific mortality (SMR 3.25, 95% CI 1.32–6.76) , and prognosis may differ according to NHL subtype . Further, ESSDAI scores at NHL diagnosis may be a useful prognostic indicator .

A number of studies have addressed clinical, serological, and genetic predictors for NHL risk. A review of these studies identified lymphadenopathy, parotid enlargement, palpable purpura, low C4 serum levels, and cryoglobulins as the most consistent NHL/lymphoproliferative disease predictors. Some studies identified splenomegaly, low C3 serum levels, lymphopenia, and neutropenia as significant prognostic factors. The detection of germinal center (GC)-like lesions in salivary biopsies may also be highly predictive of non-Hodgkin lymphoma . Genetic predictors of NHL in pSS include TNFAIP3 , BAFF , and possibly HLA DR3 .

Disease activity and B-cell hyperreactivity may play a key role in NHL-associated malignant transformation in pSS. There is no validated algorithm for the quantification of NHL risk, and no guidelines for the follow-up and management of at-risk patients. Available evidence indicates that pSS patients may have an increased risk for multiple myeloma and thyroid cancer , suggesting that these cancers could be included in surveillance monitoring.

Prevalence and incidence

A recent meta-analysis addressed the incidence rate (IR), prevalence rate (PR), gender IR, and age at diagnosis of pSS . The pooled IR of pSS was 6.92 (95% CI 4.98–8.86) per 100,000 person-years at risk. The IRs for females and males were estimated at 12.30 (95% CI 9.07–15.53) and 1.47 (95% CI 0.81–2.12), respectively, resulting in a pooled female-to-male IR ratio of 9.29 (95% CI 6.61–13.04). The overall age of pSS patients at diagnosis was 56 years (95% CI 53–60). Three studies reported the IR for pSS in different age-groups, all of which showed that the incidence of pSS increased progressively with age in women, peaking at 55–65 years, whereas in men, pSS mainly occurred in those aged 65 or older .

The pooled PR of pSS in the total population was estimated, from 18 studies, as 60.82 (95% CI 43.69–77.94) cases per 100,000 inhabitants . There was, however, substantial heterogeneity between studies for both IR and PR estimates, with country, study design, and classification criteria, all contributing factors. Large population-based studies combining meticulous case finding and case ascertainment strategies are needed to better understand the global incidence and prevalence of pSS.

Morbidity

pSS is associated with fatigue, depression, reduced quality of life, and decreased physical functioning. Pain, depression, anxiety, fatigue, and body mass index (BMI) were significant predictors of impaired utility values in health-related quality of life (HRQoL) scores in a recent study of pSS patients from the United Kingdom . Another study showed that HRQoL scores for patients are comparable to those observed for RA and SLE , traditionally considered more severe diseases. Westhoff reported that fatigue and depression predict physician visits and work disability in pSS . There are limited data on the health-care costs; however, Callaghan et al. compared health-care usage, direct health-care costs, and cost predictors in the United Kingdom, in those with pSS compared with healthy controls and RA patients. The costs in the pSS group were greater than for the RA and control groups for visits to all health-care professionals (total) as well as specific visits to the dentist, dental hospital, and ophthalmologist.

Mortality

A recent systematic review of 10 cohort studies of 7888 patients with pSS, of whom 682 died over a median follow-up of 9 years, addressed mortality causes and predictors .

The median cumulative 5- and 10-year survivals after diagnosis of pSS were 96.4% and 90.5%, respectively, and there was no statistically significant increase in all-cause mortality in patients with pSS, as compared with the general population (SMR 1.38, 95% CI 0.94–2.01). However, there was substantial heterogeneity between studies (I ² = 94%), and the authors could not exclude the possibility that pSS may be associated with increased mortality in a subset of patients with severe disease, because the two studies, which observed a statistically significant increase in mortality in pSS, were both biased toward patients with more severe disease.

Cardiovascular diseases, infections, and solid organ and lymphoid malignancies were the leading causes of mortality in seven studies included in this systematic study. It could not be determined whether these observed causes were overrepresented in patients with pSS as compared with the general population.

While lymphoid malignancies were not the leading cause of mortality, two studies showed an increase in cause-specific mortality for pSS patients with lymphoproliferative malignancy (SMR 7.89, 95% CI 2.89–17.18) and NHL (SMR 3.25, 95% CI 1.32–6.76) . The latter study reported a less favorable outcome in patients with nodal marginal zone lymphomas (NMZLs), compared to patients with MALT lymphomas or DLBCLs, although the numbers were small.

Demographic, clinical characteristics and serological risk factors associated with increased mortality include older age at diagnosis, male gender, parotid enlargement, abnormal parotid scintigraphy, systemic involvement, vasculitis, anti-La/SSB autoantibody, low C3, low C4, and cryoglobulinemia , many of which are known risk factors for lymphoma.

Mortality data are limited, and the long-term prognosis of patients with pSS is unclear. While the available data suggest that patients with pSS are not at an increased mortality risk as compared with the general population, there is increased mortality risk associated with lymphoproliferative malignancies, and possibly more severe or systemic disease.

Anti-Ro and anti-La

Antinuclear antibodies (ANAs), rheumatoid factor, and Ro/SSA and La/SSB autoantibodies are key serological findings in pSS, and form part of various criteria for the research classification of disease . ANA are present in the sera of up to 85% , and anti-Ro and anti-La autoantibodies are found in 33–74% and 23–52% of patients with pSS, respectively . It is likely that the prevalence of these autoantibodies may be biased upward in some studies, because autoantibody positivity may avoid the need for a salivary gland biopsy when applying classification criteria (see below).

The major autoantibody specificities in pSS target the intracellular antigens Ro52/TRIM21, Ro60/TROVE2, and La, which are components of ribonucleoprotein–RNA complex. Anti-La/SSB is only observed in anti-Ro/SSA-positive patients . Historically, anti-Ro/SSA, comprising both Ro52 and Ro60, was considered as a uniform autoantibody system. However, currently, it is known that Ro52 and Ro60 represent biochemically and immunologically independent autoantibodies, with different clinical associations. The prevalence of anti-Ro52 in systemic sclerosis and myositis is significantly higher than anti-Ro60, and isolated anti-Ro52 can be found in up to 37% of myositis patients . Studies have reported both a high concordance between anti-Ro52 and anti-Ro60 positivity in pSS , and also considerable discrepancies .

Multiple studies have shown that autoantibody positivity is associated with more active and systemic disease, including lymphoma risk . Anti-Ro and anti-La positivity is correlated with RF (IgM and IgA), early disease onset, glandular dysfunction, extraglandular manifestations, hypergammaglobulinemia, and other markers of B-cell activation, and CHB in neonates, following passive autoantibody transfer from the mother. These autoantibodies may be present in the serum for many years before diagnosis. One Swedish study showed that in pSS patients, who were autoantibody positive after diagnosis, at least one autoantibody specificity (ANA, RF, Ro, or La) was detected in 81% of these patients up to 20 years (median 4.3–5.1 years) before diagnosis. ANAs were the most frequent, followed by RF, anti-Ro60, anti-Ro52, and anti-La. Anti-Ro and anti-La antibodies were strongly associated with the risk of developing pSS, particularly disease onset at a younger age, and a more severe disease course . A 10-year follow-up study of UK pSS patients after diagnosis showed that while seronegative patients (ANA, RF, Ro and La negative) remained polysymptomatic, they did not develop systemic complications or serological changes. Further, 39% of these seronegative patients were given revised diagnoses over the follow up period, which included RA, SLE, mixed connective tissue disease and scleroderma .

While many studies have suggested that anti-Ro and anti-La autoantibodies represent a highly diversified, heterogeneous, and polyclonal response, evidence is emerging that pathogenic epitopes/autoantibodies may be much more restricted. The key finding that intracellular autoantigens are clustered in membrane blebs at the surface of apoptotic keratinocytes has led to the proposal that apoptotic cells serve as a source of intracellular immunogen for the production of ANAs . This, in turn, has led to the novel concept of “apotopes” of intracellular autoantigens that are expressed on the cell surface during apoptosis and which react with autoantibody. Because apotopes are targets of pathogenic autoantibodies, their detection may be more informative than standard epitope mapping. Preliminary studies support a role for apotopes of Ro and La as diagnostic markers in SLE, pSS, and CHB . Further, analysis of anti-Ro52/Ro60/La immunodominant epitope/apotope proteomes has revealed the utilization of a remarkably restricted set of autoreactive public B-cell clonotypes , implying common pathways of autoimmunity. Further research is required to define the clinical and diagnostic relevance of this novel approach.

Other autoantibodies

Fodrin is an actin-binding cytoskeletal protein that is composed of heterodimers of α and β subunits. An early study reported that autoantibodies to the α-fodrin subunit were specifically expressed in lesional salivary glands with a high sensitivity for the diagnosis of pSS . A recent meta-analysis reported that the pooled (IgG and IgA) sensitivity and specificity for anti-α-fodrin and pSS were 39.3% (CI 37.5–41.1%) and 83% (CI 81.4–84.5%), respectively, with sROC curve analysis indicative of a moderate accuracy for the diagnosis of pSS (homogeneous AUC 0.77, Q* 0.71) .

Autoantibodies to salivary protein 1 (SP-1), parotid secretory protein (PSP), and carbonic anhydrase 6 (CA6, an enzyme involved with the buffering capacity of saliva) have been reported in animal models of, and patients with, pSS . Preliminary data suggest that these autoantibodies may be markers for early pSS , and are currently marketed as the Sjö Diagnostic Test (Bausch + Lomb) for the early detection of pSS. However, there are insufficient data to determine the diagnostic utility of these autoantibodies.

IgG autoantibodies to carbamylated proteins (anti-CarP) were reported in 27% of Norwegian pSS patients . Carbamylation is a nonenzymatic posttranslational modification, in which cyanate binds to molecules containing primary amine or thiol groups to form carbamyl groups, and which may induce an autoantibody response. It was first reported in patients with increased urea levels, but is also known to be related to inflammation. The presence of anti-CarP in patients with pSS was strongly associated with increased focal lymphocytic infiltration, formation of ectopic GC-like structures in minor salivary glands, and diminished salivary gland function. While these data are, as yet, preliminary, anti-CarP may offer new possibilities for identifying patients with more active disease and at risk of developing additional comorbidity.

Autoantibodies directed against the M3 subtype of muscarinic acetyl choline receptors (anti-M3R) were first identified, in both primary and secondary SS patients, by Waterman et al. in 2000 . These autoantibodies inhibited carbachol-evoked contraction of isolated bladder detrusor muscle, consistent with functional autoantibodies that act as antagonists at the M3R and interfere with parasympathetic neurotransmission to smooth muscle. M3R are widespread on parasympathetically innervated organs, including the salivary and lacrimal glands, bladder, intestine, sweat glands, blood vessels, and iris. Many of the patients with anti-M3R antibodies had symptoms of bladder irritability, in addition to other features suggestive of autonomic dysfunction, such as constipation, fluctuating blood pressure, and dilated pupils. It is therefore plausible that antagonistic effects of anti-M3R play a key role in the development of the cardinal clinical manifestations of Sjögren’s syndrome, both in the development of sicca symptoms and other features of autonomic dysfunction . Further research into the functional and clinical significance of anti-M3R antibodies has been hindered by difficulties in developing a reliable, high-throughput serological assay. While there are many publications reporting enzyme-linked immunosorbent assays (ELISA), primarily using peptides derived from the M3R second extracellular loop, these assays are generally not translatable between laboratories, and indeed may be inherently insufficiently sensitive and/or specific to detect anti-M3R antibodies . However, a new cell-based bioassay for the detection of inhibitory anti-M3R antibodies, based on dual transfection of M3R and a luciferase reporter gene , is a promising development, which should be useful for large cohort screening studies aiming to correlate the presence in patients of inhibitory anti-M3R antibodies with symptoms of both glandular and extraglandular autonomic dysfunction.

Other, rarer, autoantibodies in pSS may define clinical subgroups . For example, antibodies to cyclic citrullinated peptides are rare in pSS and have been linked, in some cases, to the development of nonerosive arthritis. Anti-centromere antibodies are associated with a clinical phenotype intermediate between primary SS and systemic sclerosis, while antibodies against CA II are related to RTA.