CO:08:4 | Paraproteinemias in Sjögren’s disease: cryoglobulinemia and monoclonal component define distinct phenotypes with a synergistic lymphoproliferative risk
Abstract
Background. A distinctive feature of Sjögren’s disease (SjD) is the persistent activation of B lymphocytes, which may progress to lymphoma development, particularly of the MALT type. The presence of cryoglobulinemia (CRYO) and circulating monoclonal component (MC) represent two manifestations of B-cell hyperactivity and are recognized risk factors for lymphoproliferative evolution. However, it remains unclear whether CRYO and MC identify distinct clinical phenotypes. Objective. To assess whether CRYO, MC, or their combination define different SjD phenotypes in terms of disease activity (ClinESSDAI) and lymphoproliferative risk. Materials and Methods. This retrospective, multicenter study included patients enrolled by Italian centers of the GRISS (Italian Sjögren's Disease Research Group), who met the 2016 ACR/EULAR classification criteria. Patients were divided into four groups: (a) isolated MC, (b) isolated CRYO, (c) CRYO+MC, and (d) none of the above (controls). The following markers associated with increased risk of lymphoproliferative evolution were analyzed: rheumatoid factor (RF), low C4 levels, anti-La/SSB positivity, salivary gland swelling, lymphopenia, and lymph node enlargement. Disease activity was assessed based on the presence of one or more ClinESSDAI domains. Finally, the prevalence of lymphoma was evaluated across the four groups. The prevalence of risk indicators, lymphoma, and ClinESSDAI domains was analyzed for each group. Differences among groups were calculated using Fisher’s exact test, Kruskal–Wallis, and Chi-square tests. Results. A total of 1202 patients were included: 58 (4.8%) in the MC group, 32 (2.6%) in the CRYO group, 35 (2.9%) in the CRYO+MC group, and 1077 (89.7%) controls. The CRYO+MC and CRYO groups showed a significantly higher prevalence of the following lymphoproliferation-related markers: RF, low C4, anti-La, and lymph node enlargement. Salivary gland swelling and lymphopenia were more frequent only in the CRYO+MC group. [Table 1] Regarding ClinESSDAI domains, the CRYO+MC and CRYO groups exhibited a significantly higher prevalence of constitutional, cutaneous (due to purpura), renal, and peripheral nervous system (PNS) domains. Haematologic and lymphoadenopathy domains, as well as the diagnosis of lymphoma, were more frequent in the CRYO+MC group. [Table 2] Conclusions. CRYO, either isolated or associated with MC, is a marker of enhanced B-cell activity (RF, low C4, anti-La, lymph node enlargement) and predominantly affects ClinESSDAI domains consistent with a vasculitic phenotype (constitutional, cutaneous, renal, and PNS). Markers of lymphoproliferation, such as salivary gland swelling, lymphopenia, lymphoadenopathy domain involvement, and lymphoma diagnosis, are more frequent in patients with CRYO+MC. These findings suggest that the CRYO+MC combination represents the true marker of lymphoproliferative activity, conferring a significantly higher risk of lymphoma development compared with CRYO alone, and even more so compared with isolated MC.
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