Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor cross‐reactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren's syndrome

Abstract

Objective. To prospectively investigate whether mixed monoclonal cryoglobulinemia (MMC) and monoclonal rheumatoid factor (mRF)-associated crossreactive idiotypes (CRI) serve as predictive factors for the development of lymphoma in patients with primary Sjogren's syndrome (SS).Methods. One hundred three consecutive patients with primary SS were evaluated from 1986 to 1991. In all patients, the amount of cryoglobulin was measured by ultraviolet absorption at 280 nm and 260 nm. The type of cryoglobulinemia was identified by agarose gel electrophoresis, combined with immunofixation. Sera from all patients were evaluated by enzyme-linked immunosorbent assay, using the corresponding monoclonal or polyclonal antibodies, for the presence of immunoglobulins bearing the idiotypes 17109 (VdIIb associated), G-6 (V,1 associated), and 3rd SS (a rabbit polyclonal antibody raised against the Fab fragment of an IgMK mRF' from a patient with primary SS). Data analysis was performed by logistic regression.Results. Eighteen of the patients with primary SS (17.4%) had MMC during the first evaluation. There was a statistically significant correlation between the presence of MMC and a higher prevalence of autoantibodies to Ro/SS-A and LdSS-B, as well as extraglandular manifestations. During a 5-year period, 7 patients developed lymphoma. Six of the 7 (86%) had MMC before the appearance of lymphoma, compared with 12 of 96 (12.4%) of the remainder (r = 0.421, P < 0.0009).Patients who developed lymphoma had higher amounts of cryoglobulin than those who did not (mean f SD 53.4 f 44.7 mg/dl versus 26.8 f 20.6 mg/dl). CRIs 17109 and G-6 were also correlated with lymphoma development (r = 0.321, P < 0.006 and r = 0.22, P < 0.03, respectively). For both CRIs, this correlation was dependent on the presence of MMC, since a stepwise multiple comparison analysis revealed that their individual significance was abolished when their correlation with lymphoma in association with MMC was assessed.Conclusion. The determination of MMC can be used as a laboratory predictive factor for lymphoma development in primary SS. CRIs 17109 and G-6 may also be used to predict lymphoma development, especially when the monoclonal component is absent.

Mortality and causes of death in primary Sjögren's syndrome: A prospective cohort study

“…In the literature there are reports of a number of studies, mainly from southern Europe (Greece and Spain), in which cryoglobulinemia, hypocomplementemia, and lymphoma development are associated in SS (11,20,21). Other reports on lymphoma development in SS do not include information on the presence of cryoglobulins (22)(23)(24)(25).…”

Characterization of B cell lymphoma in patients with Sjögren's syndrome and hepatitis C virus infection

“…In comparison with patients with SS-HCV without lymphoma, those with lymphoma had a higher frequency of parotid enlargement and vasculitis. In primary SS, parotid enlargement is considered a highly suggestive clinical sign of lymphoma (30,31), while vasculitic features are closely associated with cryoglobulinemia (32) and lymphoma (31,33), with cryoglobulins being predictive factors for lymphoma development (34). Our results suggest a close association between cryoglobulinemic syndrome and lymphoma in patients with SS-HCV, either in its asymptomatic (circulating cryoglobulins) or symptomatic (cryoglobulinemic vasculitis) form.…”

Mixed cryoglobulinemia

“…As observed for HCV infection, the prevalence of other virus-related MC seems to show a variable prevalence among patient's series from different geographical areas [86]. Moreover, a number of clinicoepidemiological studies revealed a heterogeneous distribution of different HCV-related extra hepatic manifestations, including some autoimmune disorders such as 'primary' Sjogren's syndrome [87][88][89][90][91][92][93][94][95][96][97][98].…”

“…Cryoglobulinemic syndrome may share a number of etiopathogenetic events and clinical features with both autoimmune diseases such as autoimmune hepatitis, Sjö-gren's syndrome, and polyarthritis, and B-cell lymphomas [3,11,12,25,28,[85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100]. Therefore, a differential diagnosis should be carefully done in all patients with MC syndrome (Fig.…”

“…Cryoglobulinemic syndrome can represent a crossroads between some autoimmune diseases (autoimmune hepatitis, Sjögren's syndrome, polyarthritis, glomerulonephritis, thyroiditis, type 2 diabetes, etc.) and malignancies (B-cell lymphomas, hepatocellular carcinoma) [3,11,12,25,28,[87][88][89][90][91][92][93][94][95][96][97][98]. It is possible to observe in Differential diagnosis between mixed cryoglobulinemia and other autoimmune-lymphoproliferative disorders in the setting of HCV infection the same patient a slow progression from mild HCV-associated hepatitis to various extrahepatic manifestations (arthralgias, sicca syndrome, Raynaud's phenomenon, RF positivity, etc.…”