Primary Sjögren Syndrome (2002)

Introduction Sjögren syndrome (SS) is an 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 lachrymal glands (13). 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) (59) to a systemic process with diverse extraglandular manifestations (9,10,16,19,46,47,49). Patients with primary SS have a wide variety of hematologic abnormalities, including hemocytopenias, hypergammaglobulinemia, and monoclonal gammopathies (5). Although the clinical significance of these alterations is usually mild, some patients may present severe symptomatic cytopenias or, more frequently, malignant lymphoproliferative disorders, of which SS has the highest incidence of all autoimmune diseases (50). Studies of hematologic abnormalities in primary SS are scarce, and usually include small series of patients focusing on only some of these alterations (45,52). We conducted this study to analyze the prevalence and characteristics of the different hematologic features, both clinical and analytic, in a large cohort of Spanish patients with primary SS. (For information on the patterns of disease expression in primary SS, see Garcia-Carrasco et al [19a] in this issue.) Methods Patients Between 1994 and 2000, we retrospectively investigated the hematologic features of 380 consecutive patients with primary SS who underwent a hemogram (including hematocrit and hemoglobin values, red blood cell count, mean corpuscular volume, white blood cell count, and platelet count) and erythrocyte sedimentation rate (ESR) measurement. All patients fulfilled 4 or more of the preliminary diagnostic criteria for SS proposed by the European Community Study Group in 1993 (64) 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 (64), and clinical and serologic characteristics of all patients were collected in a protocol form. We considered as exclusion criteria coexisting systemic autoimmune diseases, hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV) infections. Immunologic studies Immunologic tests included antinuclear antibodies (ANA) (indirect immunofluorescence using mouse liver/kidney/stomach as substrates), antimitochondrial antibodies (AMA), antiparietal cell gastric antibodies (PCGA), antismooth muscle antibodies (SMA) and antiliver-kidney microsome antibodies type-1 (LKM-1) (indirect immunofluorescence), precipitating antibodies to the extractable nuclear antigens Ro/SS-A and La/SS-B (ELISA), and rheumatoid factor (RF) (latex fixation and Waaler-Rose tests). Complement factors (C3 and C4) were measured by nephelometry (Behring BNA nephelometer). Serum cryoglobulins were measured after centrifugation. Blood samples were obtained and kept at 37 °C for 30 min before separation. Serum was prepared by centrifuging at 37 °C for 10 min at 2,500 rpm. Fresh, centrifugated serum was incubated at 4 °C for 7 days after collection, and examined for cryoprecipitation. IgG and IgM anticardiolipin antibodies (aCL) were estimated by an ELISA technique as described by Gharavi et al (20) with minor modifications (8). The lupus anticoagulant (LA) was measured by coagulation assays following the recommendations of the subcommittee on LA of the Scientific and Standardisation Committee of the International Society of Thrombosis and Hemostasis (7). Statistical analysis Chi-square and the Fisher exact tests were applied to analyze qualitative differences. For comparison of quantitative parameters, the Student t test was used in 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 using the SPSS program. Results General characteristics The cohort consisted of 354 (93%) female and 26 (7%) male patients (female:male ratio, 14:1). Mean age at the onset of symptoms attributable to the disease was 52.3 ± 0.83 years (range, 15–87 yr), and at the time of protocol inclusion was 58.9 ± 0.72 years (range, 16–87 yr). Disease evolution at inclusion ranged from 2 to 480 months (mean, 76.0 ± 4 mo). Three hundred seventy (97%) patients presented xerostomia, 352 (93%) xerophthalmia, and 70 (18%) parotidomegaly. Moreover, 334 of 353 (95%) were positive (according to European criteria) for ocular diagnostic tests (Schirmer test and/or rose Bengal staining), all presenting xerophthalmia, while the remaining 19 patients with negative ocular tests did not complain of clinical features of dry eye. Parotid scintigraphy was positive in 240 of 310 (77%) patients, and salivary gland biopsy showed lymphocytic infiltrates (grade 3 or 4) in 165 of 222 (74%) patients. The main extraglandular features were articular involvement in 139 (37%) patients, Raynaud phenomenon in 58 (15%), autoimmune thyroiditis in 58 (15%), cutaneous vasculitis in 46 (12%), pulmonary involvement in 35 (9%), peripheral neuropathy in 29 (8%), and renal involvement in 24 (6%). Finally, the main immunologic features were ANA in 275 of 376 (73%) patients, anti-Ro/SS-A in 147 of 375 (39%), RF in 138 of 374 (37%), anti-La/SS-B in 99 of 375 (26%), hypocomplementemia in 46 of 353 (13%), and cryoglobulinemia in 26 of 290 (9%). Hemogram analysis The hematologic profile showed the existence of hemocytopenia in 125 (33%) patients, bicytopenia in 39 (10%), and pancytopenia in only 5 (1%) patients. The most frequent cytopenias were anemia in 76 (20%), leukopenia in 59 (16%), and thrombocytopenia in 48 (13%) patients (Table 1).TABLE 1: Hematologic features in patients with primary Sjögren syndromeRed blood cell count: Seventy-six (20%) patients had anemia (defined as hemoglobin <11 g/L in both men and women), although only 15 (4%) presented severe anemia (hemoglobin <9 g/L). Seventy-one (93%) patients showed normochromic normocytic anemia, 3 (4%) microcytic anemia, and the remaining 2 (3%) macrocytic anemia. In 21 patients the cause of the anemia was clearly identified: gastrointestinal bleeding (n = 12), chronic atrophic gastritis (n = 2), lymphoproliferative diseases (n = 2), hemolytic anemia (n = 1), myelodysplastic syndrome (n = 1), aplastic anemia (n = 1), and other causes (n = 2). In the remaining 55 patients, no cause other than primary SS was identified. We cannot exclude a subclinical hemolysis in these patients since Coombs test was not performed in all of them, although no evidence of biologic hemolysis was detected. Compared with patients with normal hemoglobin values, those with anemia presented a higher prevalence of renal involvement (12% vs 5%, p = 0.035), cutaneous vasculitis (22% vs 10%, p = 0.005), peripheral neuropathy (22% vs 4%, p = 0.001), ANA (86% vs 70%, p = 0.006), anti-Ro/SS-A (58% vs 34%, p < 0.001), anti-La/SS-B (40% vs 23%, p = 0.005), RF (52% vs 33%, p = 0.003), cryoglobulinemia (20% vs 6%, p = 0.002), and hypocomplementemia (24% vs 10%, p = 0.02), in the univariate analysis, although only peripheral neuropathy and ANA were significant independent variables in the multivariate analysis (Table 2).TABLE 2: Main clinical features, diagnostic tests, and immunologic markers according to hematologic profileWhite blood cell count: Fifty-nine (16%) patients had a leukocyte count <4 × 109/L, although only 1 (0.2%) presented severe leukopenia (count <2 × 109/L). When SS patients were compared according to the presence or absence of leukopenia, those with leukopenia presented a higher prevalence of peripheral neuropathy (15% vs 6%, p = 0.029), anti-Ro/SS-A (72% vs 33%, p < 0.001), anti-La/SS-B (43% vs 23%, p = 0.003), RF (64% vs 32%, p < 0.001), cryoglobulinemia (21% vs 7%, p = 0.004), and hypocomplementemia (23% vs 11%, p = 0.028) in the univariate analysis, although only anti-Ro/SS-A antibodies and RF were significant independent variables in the multivariate analysis (see Table 2). The leukocyte differential count was carried out in 268 patients: lymphopenia (<1 × 109/L) was found in 23 (9%) patients, neutropenia (<1.5 × 109/L) in 19 (7%), eosinophilia (>5%) in 31 (12%), monocytosis (>10%) in 8 (3%), and lymphocytosis (>55%) in 2 (1%). Patients with lymphopenia presented a higher prevalence of renal involvement (13% vs 3%, p = 0.045) and anti-La/SS-B (39% vs 19%, p = 0.031) in the univariate analysis; both variables were significant independent variables in the multivariate analysis. Those with eosinophilia presented a lower prevalence of cutaneous vasculitis (0% vs 15%, p = 0.02) and positive salivary gland biopsy (50% vs 79%, p = 0.025) in the univariate analysis, although only positive salivary biopsy was a significant independent variable in the multivariate analysis (see Table 2). Finally, no clinical or immunologic differences were detected in patients according to the presence of neutropenia. Platelet count: A platelet count <150 × 109/L was found in 48 (13%) patients, although only 3 (0.4%) presented severe thrombocytopenia (<50 × 109/L). When SS patients were compared according to the presence or absence of thrombocytopenia, those with thrombocytopenia presented a higher prevalence of renal involvement (15% vs 5%, p = 0.021) and anti-La/SS-B (40% vs 25%, p = 0.035) in the univariate analysis, with both variables being significant independent variables in the multivariate analysis (see Table 2). ESR measurement ESR >50 mm/h was found in 82 (22%) patients, and was higher than 100 mm/h in 15 (4%) patients. When compared with patients with ESR <50 mm/h, those with ESR >50 mm/h presented a higher prevalence of thyroiditis (23% vs 13%, p = 0.038), renal involvement (12% vs 5%, p = 0.022), cutaneous vasculitis (21% vs 10%, p = 0.011), peripheral neuropathy (13% vs 6%, p = 0.037), positive scintigraphy (87% vs 75%, p = 0.043), positive salivary gland biopsy (86% vs 71%, p = 0.043), ANA (89% vs 69%, p < 0.001), anti-Ro/SS-A (67% vs 31%, p < 0.001), anti-La/SS-B (52% vs 19%, p < 0.001), RF (69% vs 28%, p < 0.001), cryoglobulinemia (16% vs 6%, p = 0.024), and hypocomplementemia in the univariate analysis, although only anti-La/SS-B and RF were significant independent variables in the multivariate analysis (Table 4). We found a close correlation (p < 0.001) between the values of hemoglobin, leukocyte count, and platelet count. In addition, ESR values also correlated with hemoglobin values (p < 0.001) (Table 3).TABLE 4: Main clinical and immunologic SS features according to presence of elevated ESR, hypergammaglobulinemia, hypogammaglobulinemia, and positive monoclonal IgTABLE 3: Simple linear correlation (Pearson coefficient) between hemoglobin values, white cells and platelet counts, ESR, and gammaglobulin valuesAnalysis of serum globulins The percentage of plasmatic was in of patients (see Table of plasmatic was detected in (22%) patients, being in 15 and of plasmatic was detected in 37 The analysis of the in patients with showed of IgG in of in and of IgM in was in 3 patients: 2 presented a variable immunodeficiency and 1 a g/L). The of the remaining serum globulins were in patients: higher values of were detected in 46 patients, higher values of (>10%) in (20%), and higher values of in When SS patients were compared according to the presence or absence of hypergammaglobulinemia, those with presented a higher prevalence of (16% vs 5%, p = cutaneous vasculitis (23% vs 11%, p = peripheral neuropathy (20% vs 7%, p = Raynaud phenomenon vs 11%, p = positive scintigraphy vs p = positive salivary gland biopsy vs p = 0.005), ANA vs p < 0.001), anti-Ro/SS-A vs 25%, p < 0.001), anti-La/SS-B vs 13%, p < 0.001), and RF (69% vs 25%, p < 0.001) in the univariate analysis, although only anti-Ro/SS-A and RF were significant independent variables in the multivariate analysis (see Table 4). In addition, gammaglobulin values were correlated with ESR values (p < 0.001), hemoglobin values (p < 0.001), and leukocyte count (p = 0.02) (see Table Patients with showed a lower of ANA vs p = anti-Ro/SS-A vs p < 0.001) and anti-La/SS-B vs p = 0.001) antibodies in the univariate analysis, although of these variables was significant in the multivariate analysis (see Table 4). antibodies We for antibodies in patients, and found in 24 (13%) (see Table IgG anticardiolipin antibodies (aCL) were detected in (7%), patients positive in 8 and positive in and in 5 (3%) positive in positive in and positive in LA was detected in patients. these patients with primary SS and positive only 1 fulfilled diagnostic criteria for In addition, SS patients were compared according to the presence or absence of no differences in the or immunologic characteristics were detected. was performed in the of patients. were detected in 24 (22%) patients: (n = (n = (n = 2), (n = 2), (n = 1), and monoclonal (n = (see Table Compared with SS patients with negative those with positive presented a higher prevalence of pulmonary involvement vs p = and cryoglobulinemia (23% vs 4%, p = in the univariate analysis; both variables were significant independent variables in the multivariate analysis (see Table 4). the of primary SS, 7 (3%) patients lymphoproliferative 5 and 2 All were female with a mean age of 58 years (range, yr). The main clinical features at were (n = (n = (n = (n = 2), (n = 2), and (n = 2). The main hematologic abnormalities were (n = lymphopenia (n = ESR >50 mm/h (n = anemia (n = 2), thrombocytopenia (n = 2), and leukopenia (n = 2). The immunologic profile showed ANA in 5 of cryoglobulinemia in 2 of 4 hypocomplementemia in 2 of anti-Ro/SS-A in 1 of and RF in 1 of Finally, was performed in only 1 In this we found a and variety of hematologic abnormalities in a large series of patients with primary SS. was detected in of patients, in ESR >50 mm/h in monoclonal in anemia in leukopenia in thrombocytopenia in 13%, in 13%, and eosinophilia in are studies of hematologic abnormalities and significance in primary SS. and were the to analyze the abnormalities of both primary and SS patients in an study including hematologic serum and 30 years a focusing on the hematologic manifestations of primary SS was performed in a small series of patients. et al found a wide of hematologic as positive tests, thrombocytopenia, myelodysplastic hemolytic anemia, aplastic anemia, and red cell et al the prevalence of some hematologic in a series of patients and found in of patients, anemia in leukopenia in and hemolytic anemia in The of the main series of patients with primary SS (Table that anemia was detected in of patients, leukopenia in of and thrombocytopenia in of patients. The prevalence of and the variety of hematologic abnormalities are similar to those in patients with systemic lupus is that some of these hematologic alterations are included in the diagnostic not in the criteria for and in patients with primary SS, studies have described the of leukopenia lymphopenia anemia and thrombocytopenia with positive We have these In the multivariate statistical analysis, anemia was to leukopenia to anti-Ro/SS-A and and lymphopenia and thrombocytopenia to the between positive and cytopenias in primary SS, that SS patients a with a higher prevalence of evidence a possible by which anti-Ro/SS-A and La/SS-B antibodies may the of these expression of the Ro/SS-A and La/SS-B mainly in the by is possible that some with a may the of patients with SS, cell expression of Ro/SS-A and La/SS-B to an of blood cells In this we have found a higher prevalence of in those patients with primary SS and normocytic anemia was the most of anemia found in SS patients, in with studies of anemia, as hemolytic anemia, aplastic anemia, and myelodysplastic were also found in SS patients. In the 35 with some of these of anemia in patients with primary SS have (Table of anemia in patients with primary SS, significant hemolysis is in primary SS, with only 23 of hemolytic anemia of which only are described (Table these patients presented to anemia with a significant of hemoglobin All 1 with as was in 2 patients, in and in The of these patients was with of hemoglobin values in due to the of hemolytic anemia in patients with primary SS, we that hemolytic assays Coombs performed only in those SS patients with clinical evidence of anemia and/or biologic evidence of hemolysis and In these patients, is and of patients with primary SS and hemolytic anemia, are of other of anemia in primary SS. We have described 2 patients with myelodysplastic and et al 2 these 4 patients were is possible that and primary SS in these patients. We have also described 1 SS with aplastic anemia, an in only 4 these patients, 1 to was to and to A while et al described a to and who an The remaining aplastic anemia 3 months after the of an other of anemia, as red cell or anemia have described in patients with primary SS. was found in of patients. studies have leukopenia in of the patients We found a between leukopenia and positive immunologic markers as anti-Ro/SS-A and as We that a hematologic described in was found in of patients. patients presented a higher of anti-La/SS-B described by et al an of SS in only 5 was found in of patients (Table clinical significance is and no clinical or immunologic SS features were et al described 2 patients, 1 with a neutropenia not and the with coexisting in with both platelet and We found no with severe which is described in autoimmune diseases in and in primary SS in with only 2 in the Finally, eosinophilia was found in of patients. et al described eosinophilia in patients with both primary and SS. The clinical significance of eosinophilia in primary SS is and of a lower positive in the salivary gland biopsy Patients with primary SS and count, was found in of patients. studies have described thrombocytopenia in of the patients (see Table We found a significant between thrombocytopenia and anti-La/SS-B as found in a study In a of the et al patients with thrombocytopenia and SS, of with primary SS. of these patients showed normal to of and more than showed et al described 7 patients with thrombocytopenia who were and with a higher prevalence of positive anti-La/SS-B and Three of these patients had positive antibodies with et al described 4 patients with 2 of had an onset of thrombocytopenia that to and with in SS patients to by peripheral platelet due to or with a similar to that described in patients thrombocytopenia is in primary SS, with only (Table of 5 presented clinical features as cutaneous (n = 2), (n = 2), and bleeding (n = 2). All patients were with associated with in 2 and as in A was in most patients, although 1 was to and and to thrombocytopenia in patients with primary SS, was in of SS patients in the by et al and et al studies described from to ESR or were hematologic features found in SS patients and were to the main immunologic SS markers as and anti-La/SS-B are described in et al found that the mean serum IgG was higher in patients and that ESR was higher in and patients. et al that anti-Ro/SS-A and anti-La/SS-B were correlated with In addition, a close was found in study between ESR values and the of that the ESR in patients with primary SS may to higher of ESR may a hematologic in primary SS that those patients with an not only to the presence of and RF also to as and is that study found in of patients, as described by et al in 2 patients with SS who had In patients with hypogammaglobulinemia, 3 features 4 of 8 patients with had hypogammaglobulinemia, with the of lymphoproliferative (50). patients showed a percentage of positive as ANA anti-Ro/SS-A and anti-La/SS-B (3%), which a different immunologic of this of patients or the existence of negative due to of we 3 patients with associated with primary SS, 2 of had a variable immunodeficiency and 1 a of has not described in primary SS, 7 of of and 7 with have (Table We only in those SS patients with that those with immunodeficiency in patients with primary SS, patients with primary SS, a significant had (13%), mainly and had clinical with only 1 with syndrome and primary SS is an the other was described by et al The of the present study those of a preliminary study in patients with primary SS and the that not a of patients and to the of from in primary SS. we not for in primary SS patients a history of and/or A percentage (22%) of patients in series presented monoclonal IgG (n = and IgM (n = 4) were the most frequent detected. et al in a of the described 35 monoclonal gammopathies and 1 in patients with SS, and in patients 4 2 and 1 We correlated positive with pulmonary involvement and that presence in a with primary SS was associated with only 1 of these SS patients with monoclonal has an to may a frequent hematologic in primary SS not to the presence of an lymphoproliferative may to other manifestations as disease or cryoglobulinemia that may with or the of these patients more than that of patients monoclonal Finally, we serum in all patients with primary SS for 2 main the of a monoclonal may the existence of an associated cryoglobulinemia in some may diverse the presence of a monoclonal and/or cryoglobulinemia is associated with a higher of lymphoproliferative diseases in patients with primary SS, as by the study of et al study 7 of primary SS patients had an was the most in with is that in patients with SS are of although the of the cells in the salivary glands are cells (50). is considered the main in the history of SS, although studies have that only (4%) of patients with primary SS (Table 1 study the incidence of which was found in 7 (7%) of patients with primary SS 5 The from an autoimmune to an may a process B is in a small percentage of patients with primary SS. The clinical of primary SS to serologic and of patients who a differential of patients with negative immunologic markers have the for while patients with higher ESR, hypergammaglobulinemia, and positive expression of an and those with monoclonal expression of an monoclonal have the highest of studies large series of patients are to analyze the incidence of in primary SS, and to the characteristics of patients with the highest of to a process that affects a of patients with primary of in patients with primary SS, We the prevalence and significance of clinical and hematologic manifestations in a large cohort of patients with primary Sjögren syndrome (SS) female and 26 male The erythrocyte sedimentation rate monoclonal and were We found a and variety of hematologic features in patients with primary SS. was detected in of anemia leukopenia (16%), and thrombocytopenia (13%) were the most In the multivariate analysis, these cytopenias were correlated with antinuclear antibodies rheumatoid factor anti-Ro/SS-A and anti-La/SS-B and elevated ESR were found in of patients and were associated with positive immunologic markers as rheumatoid and presence those patients with the highest We found some hematologic features not described in primary SS, as eosinophilia (12%), antibodies (13%), and We also the presence of lymphoproliferative and found monoclonal monoclonal in of patients. was correlated with the presence of cryoglobulins and was associated with in only 1 that the presence of monoclonal is a frequent and of primary SS. 7 (3%) of patients presented that is a process that a small and of patients with primary SS. In the of some hematologic features and close with some clinical and immunologic SS features the of hematologic manifestations in the clinical spectrum of primary SS. possible inclusion in a of the diagnostic as in criteria for systemic lupus The of this and studies that some tests antibodies of hemolytic performed in patients with primary SS presenting clinical features the following hematologic tests ESR, and serum complete the of the variety of clinical and biologic manifestations that primary SS. The for