a75 patients had leukopenia at diagnosis, 64 during follow-up

Table 25.7 Prevalence of lymphopenia and neutropenia in primary SS

a<1 × 109/L, b<1.5 × 109/L, c<0.9 × 109/L, d<2.5 × 109/L, e<1,000/mL, f<1500/mL

including large series of patients that described an association between leukopenia, anti-Ro/SS-A antibodies, and RF [1]. These findings underline the striking relationship between positive autoantibodies and cytopenias in primary SS. Some experimental studies [49, 50] have suggested a possible etiopathogenic mechanism played by anti-Ro/SS-A and anti-La/SS-B antibodies, as suggested in the etiopathogenesis of other cytopenias (AIHA, above).

The differential leukocyte count has been studied in large series of patients with primary SS. The most frequent abnormality was lymphopenia, closely followed by neutropenia (Table 25.7) [1, 12, 82]. Brito-Zerón et al. [82] reported a prevalence of neutropenia (<2.5 × 109/L) of 27%. However, when using a definition of neutrophil count <1.5 × 109/L, the prevalence fell to 14%. Neutrophil counts may oscillate between normal and low values in the majority of patients, with values between 1.5 × 109/L and 2.5 × 109/L in 60% of cases [1].

25.3.8Lymphopenia

In primary SS, lymphopenia has been associated with other cytopenias [82] and a higher prevalence of autoantibodies [83]. The cause of lymphopenia in SS is unknown. Kirtava et al. [84] reported persistently reduced CD4+ lymphocyte counts in 5% of patients with primary SS without HIV infection, a prevalence higher than that reported for any other non-HIV population group. The prevalence of CD4+ lymphopenia was higher in anti-Ro/SS-A antibody-positive SS patients, compared with seronegative and sicca patients [85]. These authors also identified anti-CD4 autoantibodies in 13% of 214 patients with primary SS, although no correlation was found between anti-CD4 antibodies and lymphopenia.

CD4 lymphocyte depletion in primary SS suggests an altered balance between CD4+ and CD8+ cells. Viral infections are typical causes of lymphopenia, and HIV infection is the prototype of viral-induced CD4+ T lymphopenia associated with lymphoma development. In 2006, Theander et al. [86] were the first to suggest that CD4+ T lymphopenia and a low CD4+/CD8+ T-cell ratio were predictor factors for the development of lymphoma in primary SS. Baimpa et al. [12] have identified lymphopenia as the only independent predictive variable for the development of any type of lymphoma other than marginal zone B-cell lymphoma (MZBCL).

Whatever the mechanism by which lymphopenia (especially at the expense of CD4+ T-lymphocytes) is induced in primary SS, it reflects a state of decreased immune surveillance. In this context, the probability of a progression from autoimmunity to a more aggressive type of lymphoma, such as diffuse large B-cell lymphoma (DLBCL), may be greater.

25.3.9Neutropenia

Neutropenia is an uncommon, but well-established, analytical finding in primary SS. It may be secondary to neoplasia, adverse drug reactions, or immune mediated. According to a recent study that analyzed the causes of neutropenia in a large series of patients with primary SS [82], the most frequent cause (90%) was idiopathic or autoimmune neutropenia, followed by neutropenia associated with neoplasia or drugs in 3% of cases. SS patients with neutropenia often have other cytopenias [82, 87, 88]; in a large cross-sectional study [1], a close correlation between hemoglobin values and leukocyte and platelet counts was found. This suggests that there may be a specific subset of patients with primary SS, probably genetically predisposed, with a higher risk of developing cytopenias. Gottenberg et al. [89] described an association between haplotype DQB1*01 and neutropenia (<1 × 109/L), while other studies have suggested a possible role of cytokine polymorphisms in the etiopathogenesis of idiopathic chronic adult neutropenia [90, 91]. The possible influence of the innate immune system has also been postulated [92].

Patients with neutropenia also have a high frequency of altered immunological markers including positive autoantibodies and low complement levels, especially those with lower neutrophil counts (< 1.5 ×109/L), who had a twofold higher prevalence of RF and a threefold higher prevalence of anti-Ro/La antibodies in comparison with patients without neutropenia [82]. The association of neutropenia with positive anti-Ro/La antibodies has been previously described for other cytopenias such as leukopenia [2, 9, 81], lymphopenia [2, 81, 83], and thrombocytopenia [83]. It is known that some viruses, such as parvovirus B19 and HCV, are linked to both primary SS and severe cytopenias [51, 93]. Abnormal Ro/La antigen expression in blood cell membranes may induce the synthesis of autoantibodies against these cells and their lysis by an antibody-mediated complement-dependent mechanism [94]. The high frequency of hypocomplementemia in neutropenic patients supports the possible role of this mechanism in the etiopathogenesis of SS-related

autoimmune neutropenia. Although a possible etiopathogenic role of antineutrophil antibodies has been suggested in the peripheral destruction of neutrophils in primary SS, the majority of studies have found no correlation between these antibodies and the neutrophil count.

In addition to the association between neutropenia and autoantibodies, an association with the development of lymphoma and infections has been recently postulated. Baimpa et al. [12] described neutropenia as a significant predictive factor for the development of lymphoma, especially MZBCL, while Brito-Zerón et al. found a higher rate of hospital admissions due to infection in patients with primary SS and neutropenia [82], especially in those with neutrophil counts less than 1 × 109/L. Therefore, these patients should be closely followed due to the high risk of infection.

According to a recent study [82], most SS patients with autoimmune neutropenia required no specific therapy, with standard antibiotic therapy often being sufficient to deal with infections. However, specific treatment with glucocorticoids, intravenous immunoglobulins, or granulocyte colony-stimulating factor (G-CSF) has been suggested in patients with severe infections or those requiring surgery [95, 96], although refractory neutropenia has also been described in primary SS despite G-CSF [97].

Severe immune granulocytopenia or agranulocytosis is uncommon in systemic autoimmune disease and particularly in primary SS, and few cases have been reported [82, 87, 88]. Agranulocytosis was found in 7/300 primary SS patients [82] and was mainly related to the development of neoplasia (5 patients); in the remaining 2 patients, the cause of agranulocytosis was not identified. The first patient presented a steady, low neutrophil count, while the other patient presented cyclic episodes of agranulocytosis, resembling cyclic neutropenia, a rare hematologic disorder not described in patients with primary SS. Two recent studies [87, 88] found a close association between agranulocytosis and positive autoantibodies and coexisting cytopenias.

Autoimmune neutropenia has also been associated with the development of large granular lymphoma (LGL), a T-cell leukemia closely associated with agranulocytosis. In fact, a recent study found that almost 25% of patients with LGL have an underlying primary SS, suggesting a closer relationship than previously suspected [98].

Treatment for agranulocytosis in primary SS is controversial, with variable results with corticosteroids, immunosuppressive treatment, or G-CSF [87, 88].

Although previous studies reported antineutrophil antibodies in patients with primary SS [99, 100], it was not until 1995 [101] that their presence was specifically analyzed in a series of 66 patients, and a prevalence of 45% reported. However, no correlation was found between the presence of antibodies and the number of neutrophils, suggesting that autoantibody production follows the release of FcRIIIb, which in turn, follows the activation of polymorphonuclear leukocytes (PMN). These authors found a significant correlation between neutropenia and the presence of non-erosive arthritis, Raynaud phenomenon, lung disease, and the presence of HLA-DR3. However, they found no correlation with serum IgG or serum PMN counts. Therefore, according to currently available data, it is not possible to establish a clear role for antineutrophil antibodies in primary SS.