NS not specified

a141 patients at diagnosis and 53 during follow-up

25.2.2Gammaglobulins

25.2.2.1Polyclonal Hypergammaglobulinemia

Polyclonal hypergammaglobulinemia is one of the most characteristic laboratory abnormalities in primary SS. It reflects the polyclonal B-cell activation implicated in the pathogenesis of the disease and provides useful analytical data that may strengthen the diagnosis of primary SS in a patient with sicca syndrome [5]. Although it has been described in both the primary and secondary forms of SS, hypergammaglobulinemia is more typical of primary SS [6, 7].

The prevalence of hypergammaglobulinemia varies according to the classification criteria and the parameter used to define hypergammaglobulinemia (Table 25.1) [1, 7–12]. Studies from the 1960s and 1970s [7, 8] reported hypergammaglobulinemia in almost 100% of patients with SS, although subsequent studies have described a lower prevalence, ranging from 22% to 42% [1, 9–12].

Hypergammaglobulinemia is closely associated with the key immunological markers of SS (RF, anti-Ro/SS-A and anti-La/SS-B autoantibodies). In 1993, Markusse et al. [13] found a correlation between hypergammaglobulinemia and the presence of anti-Ro/SS-A and anti-La/SS-B antibodies. In 1999, Davidson et al. [2] found that the mean serum immunoglobulin G concentration was higher in anti-Ro/anti-La/SS-B positive patients than in those patients who were seronegative and in those who were either RFor ANA-positive. Subsequent studies in larger series of patients [1] confirmed a correlation between hypergammaglobulinemia and the presence of the anti-Ro/SS-A antibody and RF. Baimpa et al. [12] reported a higher prevalence of hypergammaglobulinemia in patients with positivity for ANA, RF, anti-Ro/SS-A, and anti-La antibodies. In addition, a close

a16 patients at diagnosis and 15 during follow-up

relationship has been found between ESR values and the percentage of serum gammaglobulins, suggesting that raised ESR in patients with primary SS may be directly related to higher levels of circulating gammaglobulins [1].

25.2.2.2Hypogammaglobulinemia and Immunoglobulin Deficiency

The prevalence and clinical significance of hypogammaglobulinemia in primary SS have been little studied. According to two large series of primary SS patients, the prevalence of hypogammaglobulinemia ranges between 6% and 15% (Table 25.2) [1, 12]. In 1965, Bloch et al. [7] described the development of reticulosarcoma in two SS patients with hypogammaglobulinemia. In 2002, Ramos-Casals et al. [1] reported that half of the SS patients who developed lymphoma had hypogammaglobulinemia. In this study, hypogammaglobulinemia was associated with a lower frequency of autoantibodies such as ANA, anti-Ro/SS-A, and anti-La. Baimpa et al. [12] have demonstrated that hypogammaglobulinemia is associated with palpable purpura, splenomegaly, and biopsy-proven vasculitis.

Humoral immunodeficiencies have rarely been reported in patients with primary SS. Ramos-Casals et al. [1] described three patients diagnosed with humoral immunodeficiencies in a series of 252 primary SS patients; two had common variable immunodeficiency and one had selective immunoglobulin A deficiency. Additional cases of selective immunoglobulin A deficiency and immunoglobulin G-subclass deficiency have been reported [1, 14–21]. In these patients, immunoglobulin deficiency was not associated with severe infections.

25.2.2.3Circulating Monoclonal Immunoglobulins

Detection of circulating monoclonal immunoglobulins should be considered to be a marker of a potential underlying monoclonal B-cell population. Monoclonal immunoglobulins can be associated with multiple myeloma, lymphoma, or monoclonal gammopathy of undetermined significance (MGUS). Thirty years ago, studies identified free monoclonal bands within the serum and urine of SS patients [3, 22, 23]. Since then, additional studies have investigated the prevalence and clinical significance of monoclonal immunoglobulins in SS (Table 25.3). Although a preliminary study found a prevalence of 70%, subsequent studies in larger series of primary SS patients found lower figures, ranging from 8 to 25% (Table 25.3) [12, 24–26]. Monoclonal immunoglobulin G is the most frequent type of circulating monoclonal

immunoglobulin in primary SS (60%), followed by monoclonal immunoglobulin M (30%), and, less frequently, immunoglobulin A and free monoclonal bands. The most frequent type of light chain is “k” (60%). Biclonal gammopathies are uncommon in primary SS, with a prevalence of less than 1% [26].

The clinical significance of circulating monoclonal immunoglobulins in primary SS has been little studied. The first studies suggested the association of free circulating monoclonal bands with extraglandular manifestations and lymphoma [3, 22, 23]. In 2005, an observational study in a large cohort of primary SS patients [26] showed that those with monoclonal immunoglobulins had a high prevalence of extraglandular manifestations, mainly lung involvement (interstitial lung disease). In that study, patients with monoclonal immunoglobulins also had a higher prevalence of laboratory abnormalities such as anemia, hypergammaglobulinemia, elevated ESR, and cryoglobulins compared to patients without monoclonal immunoglobulins, suggesting that SS patients with monoclonal spikes immunoglobulin have a more active pattern of disease expression. The association between circulating monoclonal immunoglobulins and hypergammaglobulinemia suggests that the appearance of a monoclonal B-cell population is more frequent in patients with greater B-cell hyperactivity.

The association between monoclonal free light chains in either serum or urine and lymphoproliferation was first suggested in the 1980s [3, 23]. Walters et al. [23] reported three SS patients in whom the detection of urinary monoclonal free light chains was followed by the development of lymphoma. In 1999, a study in 37 primary SS patients with monoclonal immunoglobulins found that 8% developed multiple myeloma [25], while a recent study [26] including 35 patients with primary SS and monoclonal immunoglobulins found that 6% of patients developed lymphoma. According to these studies and the cases reported in the literature, IgMk is the most common type of monoclonal immunoglobulin associated with B-cell lymphoma and IgGk the most common type of monoclonal immunoglobulin associated with multiple myeloma.

Since the emergence of a significant quantitatively monoclonal band may be the first biological manifestation of an underlying lymphoproliferative process, the development of monoclonal immunoglobulins in a patient with primary SS should be closely monitored, and should alert the clinician to the possible presence of cryoglobulinemia and/or lymphoproliferative disease [27].

Peripheral monoclonal expression differs substantially between patients with SS associated with chronic hepatitis C virus (HCV) infection and those with primary

SS [26]. HCV-SS patients have a prevalence of circulating monoclonal immunoglobulins of 43%, with IgMk being the most common type. Monoclonal IgMk is closely related to a higher frequency of mixed cryoglobulinemia. HCV-associated SS patients with circulating monoclonal immunoglobulins show a more restrictive monoclonal expression (limited to either monoclonal IgMk or IgGl) than do patients with primary SS, who can demonstrate all types of monoclonal heavy and light chains. This suggests that HCV may play an important role in the clonal selection of specific B-cells, with a more restricted use of specific gene segments in assembling the immunoglobulin receptor variable regions [28].

25.2.3b2-Microglobulin

b2-microglobulin is a low molecular weight protein (11,700 Da) secreted by nucleated cells. It forms the light chain of the human leukocyte antigen (HLA) and binds non-covalently to various transmembrane glycoproteins such as the HLA class I molecule. It is usually found in low concentrations in serum, bodily fluids, and secretions [29], and is of proven utility in evaluating various neoplastic, inflammatory, and infectious conditions [30]. b2-microglobulin is also used in renal disorders, particularly in kidney-transplant recipients, and in patients with suspected tubulointerstitial disease.

The role of b2-microglobulin in primary SS was first analyzed in 1975 [29], when high levels were detected in the salivary glands of patients with primary SS in comparison with patients with associated SS or sicca syndrome, suggesting a close association with the degree of lymphocytic infiltration. Subsequent studies have also found higher salivary levels of b2-microglobulin in primary SS patients in comparison with sicca syndrome patients [31–33] and healthy individuals [31, 32, 34]. High levels of b2-microglobulin have been also found in tears from primary SS patients [35].

Increased serum levels of b2-microglobulin have also been found in patients with primary SS [29, 31, 32, 36, 37], systemic lupus erythematosus (SLE) [37], and healthy individuals [31, 37, 38]. An increase in serum b2-microglobulin levels in patients with sicca syndrome has also been considered a predictor of progression to primary SS [39] and has been associated with the haplotype HLA DR3 [40]. With respect to immunological markers, b2-microglobulin levels have been associated with positive anti-Ro/SS-A and anti-La/SS-B autoantibodies [2].

Some studies have suggested a close association between serum b2-microglobulin levels and extraglandular involvement [41]. Lahdensuo et al. [42] found high serum b2-microglobulin levels in patients with pulmonary emphysema and obstructive disease of the small airways, with b2-microglobulin levels being inversely proportional to the forced vital capacity (FVC), forced expiratory volume (FEV1), and carbon monoxide diffusing capacity (DLCO) values [42]. High levels of this protein have also been reported in primary SS patients with lymphocytic/neutrophilic alveolitis [43]. Some studies have also reported high levels of b2-microglobulin in