Hct hematocrit, Hb hemoglobin

a153 at diagnosis, 88 during follow-up

SS patients with renal disease. Pertovaara et al. [44] found distal tubular renal acidosis (dTRA) in 18 of 55 patients (33%) who showed elevated levels of serum b2-microglobulin. The b2-microglobulin levels correlated with hypertension and duration of dryness.

Finally, b2-microglobulin has also been associated with lymphoma development in primary SS. In 1975, Michalski et al. [29] found increased levels of b2-microglobulin in 77% of patients with SS and lymphoma or pseudolymphoma. In 2001, Pertovaara et al. [45], described b2-microglobulin as an independent predictive factor for the development of lymphoma in patients with primary SS. b2- microglobulin has also been postulated to be a predictive factor for the development of amyloidosis in primary SS [46].

25.3Hematological Abnormalities

25.3.1Normocytic Anemia

The prevalence of anemia in primary SS patients ranges between 16% and 45% (Table 25.4) [1, 7, 9, 11, 12, 47, 48]. The classification of a patient as “anemic” in this setting may be due to several factors, including the different parameters used to define anemia; the inclusion of patients with anemia secondary to causes other than SS; and the classification criteria used for SS. Only four studies have specified the causes of anemia in patients with primary SS (Table 25.5) [1, 7, 12, 47], and in these, the prevalence of anemia attributed to SS ranged from 11% to 34%. The most common type of anemia was mild, normocytic, normochromic anemia, similar to that seen in other chronic inflammatory diseases [1, 6, 8].

Recent studies have described an association between anemia and some extraglandular manifestations such as palpable purpura [12], lymphadenopathy [12], and peripheral neuropathy [1], and positive autoantibodies, mainly anti-Ro/SS-A and anti-La/SS-B antibodies [1, 9, 12], ANA [1, 12], and RF [12]. Some experimental

AHAI autoimmune hemolytic anemia, MDS myelodysplastic syndrome, PRCA pure red cell aplasia, GI gastrointestinal, CAG Chronic atrophic gastritis

aIn women bIn men

studies [49, 50] have suggested that anti-Ro/SS-A and anti-La/SS-B antibodies directly mediate the development of these cytopenias. Cell membrane expression of Ro/SS-A and La/SS-B antigens, mainly located in the nucleus, can be induced by various stimuli. It is possible that some viruses with specific bone marrow tropism may affect the bone marrow of patients with SS, inducing cell membrane expression of Ro/SS-A and La/SS-B and leading to an autoantibody-induced lysis of blood cells [47]. Ramos-Casals et al. [51] found a higher prevalence of cytopenias in patients with primary SS and past parvovirus B19 infection. It has been reported that anti-Ro/SS-A antibodies can coexist with markers of B-cell hyperreactivity (hypergammaglobulinemia, RF) and other cytopenias, thus supporting an autoimmune pathogenesis of the anemia [52].

Other causes of anemia that have rarely been reported in patients with primary SS (Table 25.5) [1, 7, 12, 47] include drug-induced anemia due to gastrointestinal bleeding [6] or bone marrow hypoplasia and renal failure. Finally, hematological neoplasia may be another cause of anemia in SS patients [9, 11, 19, 47, 52–63].

25.3.2Autoimmune Hemolytic Anemia

Although some studies consider a positive Coombs test a frequent hematological abnormality in SS (range from 22 to 47%), overt hemolysis is unusual [52]. Autoimmune hemolytic anemia (AIHA) has rarely been reported in patients with primary SS, with only 10 cases out of 327 (3%) primary SS patients reported with anemia (Table 25.5). The outcome of these patients was excellent, with improvement of hemoglobin values after receiving treatment with glucocorticoids, although immunosuppressive agents were added in some cases [18, 47, 52, 54, 55, 57].

AIHA may be the first clinical manifestation of underlying primary SS [52]. Thus, primary SS should be included in the differential diagnosis of AIHA.

The etiopathogenesis of AIHA in primary SS is unknown. Autoantibodies against red cells might play a role [54]. In addition, the abnormal expression of Ro/SS-A and La/SS-B antigens on the cell membrane may also contribute to the hemolysis [47]. This abnormal location of Ro/La antigens may be caused by external triggering factors, including cellular exposure to ultraviolet light or viral infections (such as adenovirus or viruses with specific bone marrow tropism), which might induce red blood cell lysis by autoantibodies. One case of AIHA has been reported in a newborn from a SS mother carrying anti-Ro/SS-A antibodies, suggesting a role for these autoantibodies in the etiopathogenesis of AIHA [47].

Due to the low prevalence of AIHA in patients with primary SS, hemolytic assays (haptoglobin, Coombs test) should only be performed in patients with clinical evidence of acute anemia or biological evidence of hemolysis such as the finding of spherocytosis on the peripheral blood smear and an elevation in the serum lactate dehydrogenase and bilirubin concentrations.

25.3.3Aplastic Anemia

Although the first case of aplastic anemia in SS was reported in a patient with lymphoma [58], seven additional cases not associated with lymphoproliferative disorders have been reported [47, 58–60, 64–66]. Aplastic anemia has also been described in association with other systemic autoimmune diseases, particularly SLE. This clinical occurrence is associated most commonly with immunosuppressive therapy. In primary SS, aplastic anemia represents less than 1% of the total cases of anemia [1]. Translocation q24, p23 in the gene 14q 24 (where tumor necrosis factor, a hematopoietic suppressor lymphokine, is encoded) was identified in one patient with primary SS [60]. This translocation might lead to an abnormal gene expression of tumor necrosis factor and, therefore, hematopoietic suppression [60]. Studies in vitro have identified IgG antibodies that inhibit the proliferation of bone marrow in patients with SLE [47], but there are no similar studies in patients with SS.

25.3.4Pure Red Cell Aplasia

Only eight cases of pure red cell aplasia (PRCA) have been described in primary SS [47, 67–72]. Two cases were associated with neoplasia (thymoma in one case and T-gamma large granular lymphocyte leukemia in the other) [71, 72]. PRCA was the first manifestation of primary SS in 2 patients [68, 69], and was associated with AIHA in another patient [70] who was refractory to treatment with glucocorticoids, intravenous immunoglobulins, and rituximab treatment [70].

Some in vitro studies have suggested that both serum erythropoietic-inhibitor IgG and cytotoxic lymphocytes may play a role in the etiopathogenesis of red cell

aplasia [47, 67], affecting erythroid cells at different development stages. However, another study did not confirm this hypothesis [73]. Since patients with primary SS have an increased risk of lymphoma, and considering that PRCA may be the first manifestation of leukemia (lymphocytic or lymphoblastic) or lymphoma, these patients should be followed [67].

25.3.5Myelodysplasia

Nine cases of myelodysplasia (MDS) have been reported in primary SS patients [1, 47, 74–76]. Some studies have analyzed the prevalence of systemic autoimmune diseases or rheumatic manifestations in patients with MDS [75, 77]. Castro et al. [77] found that 16 of 162 patients with MDS patients had rheumatic manifestations (mainly cutaneous vasculitis, but also primary SS in one patient). Roy-Peaud et al. [75] found systemic autoimmune diseases in 14 out of 97 patients with MDS, with primary SS being the most common diagnosis (4/14, 29%). A prospective study in 40 patients with MDS also found one patient with underdiagnosed primary SS [74].

25.3.6Pernicious Anemia

Pernicious anemia is an uncommon cause of anemia in patients with primary SS [5, 7–63, 78–80]. Baimpa et al. [12] reported that pernicious anemia due to chronic atrophic gastritis represents less than 1% of all causes of anemia in primary SS, and a previous study found a similar figure (3%) [1]. However, chronic atrophic gastritis is not always associated with the development of pernicious anemia [63]. This may be explained by the patchy pattern of chronic atrophic gastritis and the existence of mucosa free of disease. Some studies have suggested that chronic atrophic gastritis might be caused by primary SS, because mononuclear infiltrates have been found in the gastric mucosa [63]. Anti-parietal cell autoantibodies have been associated with chronic atrophic gastritis and pernicious anemia, but the majority of patients with primary SS with anti-parietal cell autoantibodies do not have anemia (see chapter 28).

25.3.7Leukopenia

Leukopenia is the second most frequently reported hematological abnormality in primary SS. The prevalence of leukopenia in primary SS ranges between 12% and 32% (Table 25.6) [1, 7, 9, 11, 12, 48]. Early studies found a close association between leukopenia and positive autoantibodies (mainly anti-Ro/SS-A and anti-La/ SS-B antibodies) [9, 81]. This association was confirmed in subsequent studies