anti-RNP antibodies in small series including patients with primary and associated SS and found a prevalence ranging between 8% and 28% [38–42]. In contrast, a recent study analyzed 55 patients with MCTD and found sicca symptoms in 23 (42%) patients and positive anti-SSA/Ro in 18 (33%) [43]. Thus, overlap syndromes between SS and MCTD occur in some patients.

28.7Antiphospholipid Antibodies

Antiphospholipid antibodies (aPL) are the most frequently detected atypical autoantibodies in primary SS (Table 28.2). One study reported a total of 134 patients with aPL [31]. In spite of the frequency with which aPL are detected, the fully expressed antiphospholipid syndrome (APS) occurs in only a minority of primary SS patients. Only 13 (10%) SS-aPL patients presented thrombotic events, 12 (9%) had thrombocytopenia, 8 (6%) had histories of fetal loss, 2 (1.5%) had livedo reticularis, and 1 (1%) had hemolytic anemia. Only 12 (9%) of the 134 SS-aPL patients fulfilled the 1999 APS classification criteria [44].

Most experts regard aPL as nonspecific immunological markers in patients with primary SS, analysis of the clinical and immunological features of these 134 patients shows potentially greater clinical relevance than previously supposed. First, these patients presented with aPL profiles that differ from those of patients with fully expressed APS, with very infrequent detection of IgM anticardiolipin antibodies [45–47]. Second, in one-quarter of these SS-aPL patients, a heterogeneous spectrum of APS-related manifestations was observed, including patients with a prothrombotic history but only one isolated positive aPL determination; patients with hematological features (mainly thrombocytopenia and, more infrequently, hemolytic anemia); and patients with aPL but with obstetric complications not included in the current classification criteria (e.g., fewer than three fetal losses).

Although only 3% of patients with primary SS have associated APS, aPL are detected in nearly 25%. In contrast, aPL are detected in 43% of SLE patients [48] and while 15% of SLE patients fulfill the APS classification criteria [48, 49].

Table 28.2 Prevalence of atypical immunological markers in patients with primary SS [31]

Haga et al. [50] found an incidence of 1.44 thromboembolic events per 100 patientsyears in SS patients, which was lower than that reported for SLE patients [51]. Fauchais et al. [4] found that positive aPL was closely related to the presence of hypergammaglobulinemia and that SS-aPL patients had a high frequency of organspecific autoimmune diseases associated with SS (thyroid disease, primary biliary cirrhosis, autoimmune thrombocytopenic purpura). The presence of cerebral white matter lesions in MRI did not correlate with positive aPL.

In summary, the coexistence of primary SS and APS should be considered an infrequent (but not exceptional) event that occurs in approximately 10% of primary SS patients who have aPL. We do not recommend routine aPL determination in patients with primary SS except in those with specific clinical (thrombosis or repeated miscarriages) or laboratory (thrombocytopenia, hemolytic anemia) features consistent with APS.

28.8Anti-Scl70 Antibodies

We have described two patients with primary SS and anti-Scl70 or anti-topoisomerase I antibodies [31]. No previous studies have analyzed the prevalence and clinical significance of these autoantibodies in patients with primary SS, with only two isolated cases being reported in patients with coexisting SS and SLE [52]. None of these four patients presented clinical features suggestive of SSc. However, clinicians should be aware of the possibility of the development of scleroderma features in patients who have these autoantibodies.

28.9Anticentromere Antibodies

In contrast to anti-Slc70 antibodies, anticentromere antibodies (ACA) seem to have a higher prevalence and greater clinical significance in patients with primary SS, with a total of 48 cases being reported [31, 53–57]. A combined analysis of these 48 patients suggests the frequent expression of a specific clinical phenotype. An analysis of the 38 well-described SS-ACA patients showed Raynaud’s phenomenon and telangiectasias, observed in 61% of the patients, to be the predominant clinical features. The principal immunological findings were comprised of high titers of ANA but a relatively low prevalence of rheumatoid factor (28%) and anti-SSA/Ro antibodies (7%). During the follow-up, limited SSc emerged in 7 (25%) of the 28 patients, with the appearance of typical cutaneous signs and sclerodactylia.

Salliot et al. [58] reported a prevalence of anticentromere antibodies of 4.7% in patients with primary SS. In general, these patients did not fulfill the classification criteria for SSc but had a higher prevalence of Raynaud’s phenomenon, peripheral

neuropathy, and other autoantibodies or autoimmune diseases – especially primary biliary cirrhosis – compared to patients without anticentromere antibodies.

We recommend routine testing for ACA in patients with primary SS who have Raynaud’s phenomenon, especially in patients with high titers of ANA and negative anti-Ro/La antibodies. A substantial portion of such patients are at risk for the development of coexistent limited SSc. Close inspection on physical examination for incipient cutaneous changes that suggest limited SSc, particularly a nailfold capillaroscopic analysis, is essential. In addition, SS-ACA patients should be monitored closely for the development of gastrointestinal or pulmonary manifestations that commonly complicate SSc.

28.10Anti-neutrophil Cytoplasmic Antibodies (ANCA)

A total of 59 patients with primary SS and positive ANCA have been reported [31]. The potential clinical significance of these autoantibodies in patients with primary SS are defined by three points: the prevalence of the different immunofluorescence patterns and enzyme immunoassay specificities; the association of these autoantibodies with specific extraglandular features of SS; and the overlap with systemic vasculitis.

ANCA were detected in 36 (19%) of 194 primary SS patients included in 4 previous studies [59–62] but only 6% in another study [31]. Eighty percent of the patients with positive immunofluorescence assays for ANCA demonstrated a perinuclear (p-ANCA) pattern. An additional 19% of the patients showed atypical patterns of immunofluorescence, and only one patient (<1%) had cytoplasmic (c-ANCA) patterns [63]. The ANCA specificities, analyzed in 20 patients by enzyme immunoassay, were reported to be myeloperoxidase in 15 cases [59, 64–67], lactoferrin in 4 cases [59], and proteinase-3 in 1 case [63].

The clinical characteristics of SS-ANCA patients, in 19 of the 59 cases, included a high prevalence of such extraglandular features as Raynaud’s phenomenon and pulmonary disease, necrotizing crescentic glomerulonephritis, peripheral neuropathy, or cutaneous vasculitis in 20–30% of patients. SS-ANCA patients had a high prevalence of other autoantibodies: 71% had high titers of ANA, anti-SSA/Ro and –SSB/ La antibodies, and/or rheumatoid factor.

Coexistent systemic vasculitis develops in only a small number of patients. One of our patients developed an associated microscopic polyangiitis [31]; two similar cases have been previously reported [63, 68]. Radaeli et al. described the coexistence of primary SS and microscopic polyangiitis in a 72-year-old woman with ulcerative jejunitis [68]. Young et al. [63] described a patient with primary SS, cavitary lung disease, and ANCA directed against proteinase 3 and causing a c-ANCA pattern of immunofluorescence, all highly consistent with Wegener’s granulomatosis.

The clinical significance of ANCA in patients with primary SS can be summarized by an overwhelming prevalence of the p-ANCA pattern. However, antibodies directed against myeloperoxidase are found in less than 20% of cases. There is a high frequency of extraglandular and immunological features among these patients, but

true ANCA-associated vasculitis emergences in only a minority of the cases. Thus, there appears to be little utility to the routine determination of ANCA in patients with primary SS, and ANCA testing should be reserved for those in whom a high index of suspicion for a true “pauci-immune” form of systemic vasculitis exists.

28.11Anti-citrullinated Antibodies

Antibodies to cyclic citrullinated peptides (CCP) are highly specific for the diagnosis of rheumatoid arthritis (RA) (95%) and have a sensitivity for RA that is on the order of 65% [69, 70]. Recent studies suggest that anti-CCP and anti-keratin antibodies are useful in discriminating SS patients with coexisting RA from those with primary SS. Goeb et al. found anti-CCP autoantibodies in only 4% of 137 women and 16% of 11 men with SS [71]. In a study of 134 patients with primary SS, Gottenberg et al. [72] found anti-CCP antibodies in 7.5% and anti-keratin antibodies in 5.2%. Other studies have confirmed that anti-CCP and anti-keratin antibodies occur in a minority of patients with primary SS, with or without evidence of erosive arthritis [73–76]. The presence of erosive arthritis and either anti-CCP or anti-keratin antibodies in a patient with primary SS likely signals the co-occurrence of two diseases, primary SS and rheumatoid arthritis.

28.12Rheumatoid Factor and Cryoglobulins

Rheumatoid factor is the second most frequently detected antibody in patients with primary SS after ANA (40–60%). Patients with rheumatoid factor positivity show a higher frequency of extraglandular and immunological features including articular involvement, cutaneous vasculitis, ANA, and anti-SSA/Ro. The results in larger studies support a key role of rheumatoid factor in the diagnosis of primary SS because this immunological marker has an independent association with most of the main clinical and immunological features of the disease [22, 77–79]. Thus, rheumatoid factor is a useful immunological test for the diagnosis of some subsets of patients with primary SS, such as those with extraglandular manifestations or with circulating cryoglobulins.

The clinical significance of cryoglobulinemia in primary SS is threefold. First, cryoglobulins are associated with a higher prevalence of extraglandular disease [79–82]. Second, patients with cryoglobulinemia are at a higher risk of B-cell lymphoma than are those who do not have cryoglobulins [79]. Third, there is a close association between cryoglobulinemia and life-threatening vasculitis. In one study, all of the primary SS patients with small-vessel vasculitis who died presented with cryoglobulinemic vasculitis [76]. Thus, the finding of cryoglobulinemia in a patient with primary SS is a marker for enhanced risks of lymphoproliferative disease, vasculitis, and early mortality.