Primary Sjögren Syndrome

Introduction Sjögren syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes due to functional impairment of the salivary and lacrimal glands (12). In the absence of an associated systemic autoimmune disease, patients with this condition are classified as having primary SS. The histologic hallmark is a focal lymphocytic infiltration of the exocrine glands, and the spectrum of the disease extends from an organ-specific autoimmune disease (autoimmune exocrinopathy) (50) to a systemic process with diverse extraglandular manifestations (11,19,42–44,47). The question that arises is whether epidemiologic factors (such as gender or age at onset of disease) or immunologic patterns, among other factors, are associated with particular disease expressions and define some specific primary SS subsets (10,22,41). Several studies have addressed this problem with results that are controversial due to the small number of patients studied or the different classification criteria applied (14,23,40). We analyzed the prevalence and characteristics of clinical and immunologic manifestations in a large cohort of Spanish patients with primary SS in order to define the different clinical and immunologic patterns of disease expression. (For information on the hematologic features of primary SS, see the article by Ramos-Casals and colleagues in this issue [42a].) Methods Patients Between 1994 and 2000, we investigated the clinical and immunologic characteristics of 400 consecutive patients with primary SS in our units. All patients fulfilled 4 or more of the preliminary diagnostic criteria for SS proposed by the European Community Study Group in 1993 (55) and underwent a complete history and physical examination. Diagnostic tests for SS (rose bengal staining, Schirmer test, parotid scintigraphy, and salivary gland biopsy) were applied according to the recommendations of the European Community Study Group (55), and clinical and serologic characteristics of all patients were collected in a protocol form. Salient features included in the protocol were 1) age at disease onset, defined as the initial manifestation clearly attributable to SS; 2) age at inclusion, defined as the age when the patient entered the protocol; 3) cumulative clinical manifestations during disease evolution (from the onset until protocol inclusion); 4) laboratory findings at protocol inclusion. Definition of clinical features The clinical manifestations evaluated were defined as follows: Articular involvement: arthralgia and/or nonerosive arthritis characterized by tenderness, swelling, or effusion involving 2 or more peripheral joints. We excluded patients with osteoarthritis, nonspecific painful processes, and chronic fatigue. Fever: axillary temperature >37.5 °C, not associated with infectious processes. Lymphadenopathy: enlarged nodes (>1 cm) in the cervical, axillary, or inguinal regions. Cutaneous vasculitis demonstrated by cutaneous purpura and/ or rash. Skin biopsy showing vasculitis when performed. Raynaud phenomenon: intermittent attacks of digital pallor followed by cyanosis and/or rubor of the fingers, toes, ears, nose, tongue, induced by exposure to cold, stress, or both, in the absence of any other associated disease or anatomical abnormality. Peripheral neuropathy: paresthesias, numbness, and/or motor defects of the lower/upper extremities confirmed by electromyography. Sural nerve biopsy showing vasculitis involving vasa nervorum when performed. Nephropathy: presence of persistent proteinuria >0.5 g/day, altered urinalysis (hematuria, pyuria, red blood cell casts), renal tubular acidosis, interstitial nephritis, or glomerulonephritis. Lung involvement: persistent cough and/or dyspnea, with chronic diffuse interstitial infiltrates on X-ray, altered pattern on pulmonary function studies, and/or evidence of pulmonary alveolitis/fibrosis in computed tomography scan. Autoimmune thyroiditis: altered thyroid function with positive antithyroidal autoantibodies. Immunologic studies Immunologic tests included antinuclear antibodies (ANA) (indirect immunofluorescence using mouse liver/kidney/stomach as substrates), antimitochondrial antibodies, antiparietal cell antibodies, antismooth muscle antibodies (SMA), and antiliver-kidney microsome antibodies type-1 (indirect immunofluorescence), precipitating antibodies to the extractable nuclear antigens (ENA) Sm, RNP, Ro/SS-A, and La/SS-B (ELISA), antineutrophil cytoplasmic antibodies (indirect immunofluorescence), antithyroglobulin and antithyroid peroxidase autoantibodies (ELISA), and rheumatoid factor (RF) (latex fixation and Waaler-Rose tests). Complement factors (C3 and C4) were measured by nephelometry (Behring BNA nephelometer) (1). Serum cryoglobulins were measured after centrifugation. Statistical analysis The chi-square and Fisher exact tests were applied to analyze qualitative differences. To compare quantitative parameters, the Student t-test was used for large samples of similar variance and the nonparametric Mann-Whitney U test for small samples. Values of quantitative variables are expressed as mean ± standard error of the mean (SEM). Statistical significance was established at p < 0.05. When several variables appeared to have statistical significance in the univariate analysis, an unconditional logistic regression analysis was performed by multivariate analysis to rule out possible confounding variables. Statistical analysis was performed by SPSS program. Results The cohort consisted of 373 (93%) female and 27 (7%) male patients (female: male ratio, 14: 1). Mean age at the onset of symptoms attributable to the disease was 52.7 ± 0.85 years (range, 15–87 yr) and at the time of protocol inclusion was 58.7 ± 0.72 years (range, 16–87 yr). Disease evolution at inclusion ranged from 3 to 480 months (mean, 74.9 ± 4 mo). The main glandular manifestations are summarized in Table 1. Three hundred and ninety (98%) patients presented with xerostomia; 371 (93%) xerophthalmia, 123 (31%) cutaneous dryness, 70 of 373 (19%) genital dryness, and 73 (18%) parotidomegaly. Moreover, 351 of 371 (95%) were positive according to the 1993 European criteria (55) for ocular diagnostic tests (Schirmer test and/or rose Bengal staining). The 20 patients with negative ocular tests did not report xerophthalmia. Parotid scintigraphy was positive in 253 of 328 (77%) patients, and salivary gland biopsy showed lymphocytic infiltrates (grade 3 or 4) in 169 of 228 (74%) patients.TABLE 1: Demographic and glandular features of 400 patients with primary Sjögren syndromeThe main extraglandular features were articular involvement in 147 (37%) patients, Raynaud phenomenon in 62 (16%), autoimmune thyroiditis in 61 (15%), cutaneous vasculitis in 47 (12%), pulmonary involvement in 37 (9%), peripheral neuropathy in 29 (7%), adenopathy in 28 (7%), renal involvement in 25 (6%), and fever in 24 (6%) (Table 2). Finally, the main immunologic features were ANA in 288 of 392 (74%) patients, anti-Ro/SS-A in 153 of 385 (40%), RF in 146 of 388 (38%), SMA in 102 of 293 (35%), anti-La/SS-B in 102 of 385 (26%), antiparietal cell gastric antibodies in 58 of 289 (20%), low CH50 in 35 of 302 (12%), and cryoglobulinemia in 27 of 293 (9%) (Table 3).TABLE 2: Extraglandular manifestations of 400 patients with primary SSTABLE 3: Immunologic features in patients with primary SSEpidemiologic subsets Male patients: Of the 400 patients with primary SS, 27 (7%) were men. Compared with women, men with primary SS presented a lower prevalence of Raynaud phenomenon (0% vs 17%, p = 0.013), autoimmune thyroiditis (0% vs 16%, p = 0.022), and anti-Ro/SS-A antibodies (15% vs 41%, p = 0.011) in the univariate analysis, although only anti-Ro/SS-A antibodies were a significant independent variable in the multivariate analysis (Table 4).TABLE 4: Frequency of main clinical and immunologic features according to epidemiologic characteristics*Young onset: In 63 (15%) patients, the onset of primary SS occurred before the age of 35 years. Patients with a younger onset presented a higher prevalence of fever (16% vs 6%, p =0.004), lymphadenopathy (19% vs 5%, p = 0.001), RF (53% vs 35%, p = 0.008), and anti-Ro/SS-A antibodies (68% vs 34%, p < 0.001) in the univariate analysis compared with patients with a disease onset after the age of 35 years, although only lymphadenopathy, fever, and anti-Ro/ SS-A antibodies were a significant independent variable in the multivariate analysis (see Table 4). Late onset: In 43 (11%) patients, disease onset occurred after the age of 70 years. Patients with an older onset presented a lower prevalence of positive ocular tests (87% vs 96%, p = 0.047) and anti-Ro/SS-A antibodies (23% vs 41%, p = 0.03) in the univariate analysis compared with patients with a disease onset before the age of 70 years, although none of these variables was a significant independent variable in the multivariate analysis (see Table 4). Long-term evolution: Ninety-five (24%) patients showed a long-term evolution of SS (more than 10 years from the onset of sicca symptomatology until the protocol study). Patients with a longer SS evolution showed a higher prevalence of fever (14% vs 5%, p = 0.005), lymphadenopathy (16% vs 4%, p = 0.001), pulmonary involvement (19% vs 6%, p < 0.001), peripheral neuropathy (18% vs 4%, p < 0.001), cutaneous vasculitis (24% vs 8%, p < 0.001), and positive ocular tests (99% vs 93%, p = 0.03) in the univariate analysis compared with patients with a SS evolution shorter than 10 years, although only fever and peripheral neuropathy were significant independent variables in the multivariate analysis (see Table 4). Immunologic subsets Immunonegative patients: We found negative immunologic markers (ANA, RF, Ro/SS-A, and La/SS-B) in 84 (23%) patients. This “immunonegative” subset of SS patients showed a lower prevalence of adenopathy (1% vs 9%, p = 0.02), Raynaud phenomenon (4% vs 18%, p < 0.001), and cutaneous vasculitis (4% vs 14%, p = 0.007) in the univariate analysis, although only cutaneous vasculitis and Raynaud phenomenon were significant independent variables in the multivariate analysis (Table 5).TABLE 5: Frequency of main clinical features and diagnostic tests according to immunologic pattern*Presence of ANA not related to anti-Ro/La (ANA +/ENA−): We found positive ANA (not related to positive anti-Ro/SS-A and/or anti-La/SS-B) in 141 patients. Compared with patients with negative ANA, ANA+/ENA-patients showed a higher prevalence of pulmonary involvement (14% vs 5%, p = 0.029) and Raynaud phenomenon (13% vs 2%, p = 0.001), and a lower frequency of peripheral neuropathy (2% vs 9%, p = 0.03) in the univariate analysis; all 3 of these variables were significant independent variables in the multivariate analysis (see Table 5). Presence of RF: We found positive RF in 146 (38%) patients. These patients showed a higher prevalence of articular involvement (45% vs 33%, p = 0.017), cutaneous vasculitis (19% vs 7%, p = 0.01), and Raynaud phenomenon (21% vs 12%, p = 0.028) in the univariate analysis, although only articular involvement and cutaneous vasculitis were significant independent variables in the multivariate analysis (see Table 5). Presence of anti-Ro/La antibodies: We found positive anti-Ro/SS-A and/or anti-La/SS-B in 153 of 385 (40%) patients. These patients showed a higher prevalence of adenopathy (12% vs 4%, p = 0.007), peripheral neuropathy (11% vs 5%, p = 0.03), cutaneous vasculitis (17% vs 8%, p = 0.015), Raynaud phenomenon (26% vs 9%, p < 0.001), and positive salivary gland biopsy (84% vs 69%, p = 0.01) in the univariate analysis, although only Raynaud phenomenon was a significant independent variable in the multivariate analysis (see Table 5). Presence of cryoglobulins: We found detectable cryoglobulins in 27 of 293 (9%) patients. These patients showed a higher prevalence of parotidomegaly (41% vs 7%, p = 0.02), adenopathy (23% vs 6%, p = 0.017), cutaneous vasculitis (48% vs 11%, p < 0.001), peripheral neuropathy (26% vs 6%, p = 0.003), and Raynaud phenomenon (33% vs 13%, p = 0.01) in the univariate analysis, although only adenopathy and cutaneous vasculitis were significant independent variables in the multivariate analysis (see Table 5). Other clinical subsets Sicca-limited disease: Clinically, 139 (35%) patients presented only sicca symptomatology (without extraglandular features) while the remaining 261 (65%) presented a systemic process with diverse extraglandular manifestations. When SS patients were compared according to the existence of extraglandular involvement, those with a sicca-limited disease presented a lower prevalence of ANA (66% vs 78%, p = 0.016), anti-Ro/SS-A (32% vs 43%, p = 0.039), anti-La/SS-B (19% vs 30%, p = 0.029), RF (29% vs 42%, p = 0.011), and cryoglobulinemia (4% vs 12%, p = 0.019) in the univariate analysis, although none of these variables was statistically significant in the multivariate analysis (Table 6).TABLE 6: Frequency of main clinical and immunologic SS features according to existence of extraglandular featuresFulfillment of the 1996 European criteria: All diagnostic tests included in the European criteria were performed in 298 patients. Of these patients, 253 (85%) fulfilled the more restrictive 1996 European criteria (56), while the remaining 45 patients fulfilled only the 1993 criteria (55). When SS patients were compared according to the criteria fulfilled, those who fulfilled only 1993 criteria showed a lower prevalence of peripheral neuropathy (0% vs 10%, p = 0.019), positive scintigraphy (64% vs 82%, p = 0.02), ANA (61% vs 81%, p = 0.005), RF (19% vs 48%, p < 0.001), cryoglobulinemia (0% vs 13%, p = 0.017), and hypocomplementemia (0% vs 17%, p = 0.001) in the univariate analysis, although none of these variables was statistically significant in the multivariate analysis (Table 7).TABLE 7: Frequency of main clinical and immunologic SS features according to fulfillment of SS criteria in 298 patients with all diagnostic testsDiscussion In 1965, Bloch et al (8) gave an extensive description of 62 patients with a relatively unknown entity named “Sjögren syndrome,” characterized by sicca symptomatology and articular involvement. The authors included both patients with associated autoimmune diseases rheumatoid and patients with SS who presented more extraglandular features as neuropathy and pulmonary The report of Bloch et (8) was the to define the existence of the of SS. years we have analyzed the clinical and serologic characteristics of 400 patients with primary SS, the studied to our We have confirmed primary SS is a systemic autoimmune disease that affects of age with xerophthalmia, ANA, and RF the et al found a similar epidemiologic in a of 261 patients with of and a mean age at of years. of the findings of the is the description of primary SS as a disease that in on specific or immunologic studies have that age at onset disease of some autoimmune diseases In primary SS, studies of and have that the clinical and immunologic in from the disease in patients, with a higher frequency of specific clinical manifestations or and positive autoantibodies. In our we found a higher frequency of fever, and anti-Ro/SS-A antibodies in SS patients with a disease onset lower than 35 years. et al found that (24%) of SS patients with a disease onset lower than 45 years a higher frequency of and RF, and et al found a higher prevalence of anti-Ro/SS-A and RF in a SS that younger SS onset is associated with immunologic expression. the for this in the of the disease is factors and in or of an a In we have analyzed in patients with primary SS and found that patients the disease onset vs yr) In our showed that an onset of primary SS yr) is not (11% of our The clinical of primary SS in onset patients is similar to that of younger patients, although the prevalence of some extraglandular and immunologic features was lower in patients This lower of immunologic markers in patients of the is that in the results of diagnostic tests were older and younger patients, that these tests salivary gland biopsy) have the diagnostic in older patients as in younger The clinical of primary SS in our male patients is similar to that in female patients, although the prevalence of specific extraglandular manifestations as Raynaud cutaneous or renal involvement was the 3 studies performed in patients showed that men and the for extraglandular while et al found a lower prevalence of arthritis and Raynaud phenomenon in male patients (Table the immunologic manifestations of primary SS, and we found a lower frequency of anti-Ro/SS-A in male patients in the multivariate a lower prevalence of immunologic features in 2 (see Table et al found a lower frequency of anti-Ro/SS-A and anti-La/SS-B antibodies in male patients, and et al a lower prevalence of RF and male SS patients a lower to extraglandular although the of studies have not found statistical and have a lower immunologic in a lower frequency of anti-Ro/SS-A and immunologic manifestations in male patients with primary SS, and The of the 1993 European criteria (55) a of primary SS with negative immunologic of primary SS was in 1996 as a subset of chronic In our we found 84 patients with a negative immunologic ANA, RF, and The analysis of this “immunonegative” subset of primary SS patients showed a lower frequency of extraglandular cutaneous vasculitis and Raynaud studies have different and patients in the results of diagnostic tests in our were and patients, that the immunologic not to the of diagnostic is to this subset is an or primary SS or a of this autoimmune disease, as in other autoimmune diseases as systemic We the as this subset not any statistical in the prevalence of sicca symptomatology and for the diagnostic salivary gland the of primary SS is We a immunologic subset with a clinical Of the 288 patients with positive ANA, 141 negative anti-Ro/La This subset of patients showed a higher frequency of specific extraglandular as pulmonary involvement and Raynaud of the systemic autoimmune diseases is the of evolution from disease to and is possible that some of these patients to a disease other than primary SS as systemic or as by et al We found 146 (38%) patients with positive These patients showed a higher frequency of extraglandular and immunologic features in the as articular involvement, cutaneous ANA, and These results a possible of RF in the of primary SS, this immunologic an independent statistical with of the main clinical and immunologic SS as by studies RF a immunologic test for the of some subsets of patients with primary SS, as those with extraglandular manifestations or with We found a higher prevalence of extraglandular features in those patients with primary SS and positive studies have found similar results in of patients, with a positive anti-Ro/La antibodies and clinical features lymphadenopathy cutaneous vasculitis and involvement a higher than in salivary gland biopsy and serologic markers RF and cryoglobulins The subset of patients with primary SS and anti-Ro/La antibodies the and of the In these patients, a more clinical to and of extraglandular we that the presence of not a for primary SS, as presence a specific subset of the we found that some of the subsets in our were mainly (85%) of the male patients were as were (77%) of the 43 patients with a SS onset and of patients with a sicca-limited The inclusion of positive anti-Ro/La antibodies as an for primary SS this to a specific subset of patients, male patients, those with a and those extraglandular Finally, we found a higher prevalence of of the extraglandular features in patients with cryoglobulins a in the systemic of the studies have confirmed the of cryoglobulins as an in primary SS. et al that cryoglobulinemia and RF used as laboratory factors for in SS, and et al that the presence of and cryoglobulinemia were the of and The of cryoglobulinemia in the extraglandular features of patients with primary SS to although in a we found that of patients with cryoglobulinemia and SS presented an associated of our patients presented extraglandular features while the remaining a the (Table we found lower of the main extraglandular manifestations in our patients than in patients in studies This due to several factors, the of extraglandular our we did not patients with the existence of or the of patients with associated presented systemic autoimmune and the different criteria used for SS Compared with patients who fulfilled the more restrictive 1996 European criteria (56), those who fulfilled only the 1993 criteria (55) negative salivary gland biopsy and anti-Ro/La showed a of primary SS, with a lower frequency of extraglandular and these patients fulfilled a of 4 of the 1993 European and sicca symptomatology by the diagnostic was not related to or in these patients is to a disease other than primary SS, and only studies a clinical of extraglandular and different criteria used for the of primary SS to different of the The criteria are more those patients with the extraglandular and immunologic expression. In the 1993 European criteria (55) a of SS with negative salivary gland biopsy and negative are the 1996 European criteria (56), the existence of positive salivary gland biopsy or positive anti-Ro/La as We that these criteria are the for the of primary SS, although in of the results of the we ANA and RF to anti-Ro/La antibodies in the immunologic We that a patient with xerophthalmia, positive ocular positive parotid scintigraphy, and positive negative classified as having primary SS in the absence of systemic autoimmune diseases (such as rheumatoid systemic although this subset of patients a long-term to a possible evolution to other systemic autoimmune The low frequency of the extraglandular features in this the relatively of the disease by et al that only 4 (19%) of patients with primary SS followed for a of 10 years autoimmune and defined primary SS as an autoimmune disease characterized by a and relatively et al found that patients extraglandular features were to and that the clinical is complete at and et al a of symptoms years. In primary SS is than other systemic autoimmune diseases as and rheumatoid and the of patients on the from the sicca involvement, using a involving diverse In this we analyzed the clinical and serologic characteristics of 400 patients with primary Sjögren syndrome to our the to We confirmed primary SS is a systemic autoimmune disease that affects of xerophthalmia, antinuclear antibodies and rheumatoid factor (RF) are the We that several other manifestations not included in the 1993 European criteria as articular involvement antismooth muscle antibodies (35%), parotidomegaly Raynaud phenomenon (16%), autoimmune thyroiditis (15%), cutaneous vasculitis (12%), and hypocomplementemia were of the of the is the description of primary SS as a disease that expressed in on specific or immunologic We found a immunologic in SS patients with a younger onset and a lower in male patients. the multivariate analysis showed that the presence of any of 4 immunologic markers (ANA, RF, is statistically related to the existence of or more of the main extraglandular features of primary SS, as lymphadenopathy articular involvement cutaneous vasculitis pulmonary involvement and Raynaud phenomenon (ANA and In the subset of primary SS patients presented a lower prevalence of the main extraglandular manifestations. In clinical patients with primary SS and positive immunologic features the subset of patients a more specific with to the of systemic manifestations. Clinically, we 2 main patterns of disease in our cohort of patients with primary a subset of patients with a disease to glandular involvement and with a lower frequency of immunologic and extraglandular a subset of patients with a involvement the sicca involvement with a higher presence of immunologic and extraglandular manifestations. is that in the of diagnostic salivary gland were the 2 SS is a systemic autoimmune disease, clinical expressed in some patients a sicca while have a systemic disease with diverse and extraglandular This subset is by the used of diagnostic while those patients with a sicca-limited disease, and patients, are more using the 1993 European The in the clinical of primary SS in this that our of this systemic autoimmune disease is the 1993 European criteria the clinical of primary SS, we the of primary SS the presence of of these 2 classification criteria: 1) a positive salivary gland biopsy or 2) a positive test (ANA, RF, and/or anti-Ro/La salivary biopsy was negative or not performed. the 1996 criteria the inclusion of ANA and in our the criteria for the of primary SS. The authors for