Crioglobulinemia

COGNITIVE IMPAIRMENT IN PATIENTS WITH HCV-RELATED MIXED CRYOGLOBULINEMIA.

Laura Origgi, Stefano Zago, Massimo Vanoli, Marianna Curioni, Franco Capsoni, Raffaella Scorza Milan, Italy

Cerebrovascular accidents, seizures or other symptoms of overt central nervous system (CNS) involvement seldom occur in patients with mixed cryoglobulinemia (MC), but mild symptoms (dizziness, equilibrium impairment, headache) that could be related to a slight CNS involvement are frequent.

In patients with other immunological diseases, such as Systemic Lupus Erithematosus, cognitive dysfunction is often the first or the only symptom of CSN involvement, so we decided to assess the prevalence of cognitive impairment in patients with HCV-related MC.

Twenty-eight MC patients (5 males, 23 females), positive for anti-HCV antibodies and HCV-RNA, gave their consent to the study. Their mean age was 65 years (range 47-80). Thirteen patients (48%) were infected with HCV genotype 1b, 12 (44%) with type 2, 1 (4%) with type 3 and 1 with type 5a. Complete clinical data, including risk factors for vascular disease, were collected.

The following tests were administered: MMSE, Attentional Matrices, Raven's Coloured Matrices, Digit Span, Short Story Recall, Paired Associate Learning, Corsi's Span, Learning a Spacial Sequence, Token Test, Boston Naming Test, Verbal Fluency from Category, Verbal Fluency from Letters, Calculation Test, Oral Apraxia, Ideomotor Apraxia, Constructional Apraxia Test, Street's Completion Test.

Cognitive impairment was identified in 6 patients (21%), while 14 patients (50%) had mild imperfections in their performance, not suggestive of cognitive dysfunction.

No relationship was found between cognitive impairment and the presence of other neurological symptoms (clinical history of cerebrovascular accidents, headache, dizziness, depression). Cognitive dysfuncion was not statistically related to cigarette smoking, arterial hypertension, hyperlipidemia, diabetes mellitus, presence of anticardiolipin antibodies or anti-b2GPI antibodies, cryocrit and C3 or C4 values or differences in HCV genotype. Five of the six patients with cognitive impairment, when asked before their consent to the administration of the tests, denied having memory defects.

Our results suggest that cognitive impairment is frequent (21%) in HCV-related MC patients and is often unperceived by the patient. In our series of patients, cognitive dysfunction was not significantly related to the most frequent risk factors for vascular disease, so we believe that the impairment could actually be due to CNS involvement in MC.

 

LYMPHOPROLIFERATIVE DISEASES IN PATIENTS WITH CRYOGLOBULINEMIA: CLINICAL DESCRIPTION OF 27 CASES.

Manuel Ramos-Casals, Mario Garcia-Carrasco, Olga Trejo, Jordi Yagüe, Gloria de la Red, Victor Gil, Ricard Cervera, Josep Font, Miguel Ingelmo Barcelona, Spain and Barcelona, Spain

OBJECTIVE. To determine the prevalence of lymphoproliferative diseases in a large series of patients with cryoglobulinemia and to investigate its association with HCV infection and/or systemic autoimmune diseases.

PATIENTS. We analyzed 443 consecutive patients with cryoglobulinemia, who tested positive for circulating cryoglobulins in our Department of Immunology between 1991 and 1999. We retrospectively analyzed the existence of lymphoproliferative disorders in these patients.

RESULTS. Twenty-seven (6%) patients (15 male and 12 female) developed lymphoproliferative diseases, with a mean age at diagnosis of 61 years. Eighteen (67%) patients presented non Hodgkin’s lymphoma (NHL), 2 Hodgkin’s lymphoma, 2 chronic lymphocytic leukemia, 1 chronic myelocytic leukemia, 1 multiple myeloma, 1 Waldestrom’s macroglobulinemia, 1 monoclonal gammopathy and 1 Castleman’s disease. Only 8/27 (30%) patients showed clinical features of cryoglobulinemic syndrome. Fourteen (52%) patients showed HCV infection and 12 (44%) an associated systemic autoimmune disease, mainly Sjogren’s syndrome (n=5), systemic lupus erythematosus (n=4) and polyarteritis nodosa (n=2).

CONCLUSION. Non-Hodgkin’s lymphoma was the most-frequently found hematological process in cryoglobulinemic patients. HCV infection was detected in half the patients and SS was the most-frequently associated systemic autoimmune disease. We found a close relationship between NHL, HCV and systemic autoimmune disease in cryoglobulinemic patients.

 

CLINICAL SIGNIFICANCE OF ANTIMITOCHONDRIAL ANTIBODIES IN SYSTEMIC AUTOIMMUNE DISEASES: AN EARLY MARKER OF INCIPIENT, ASSOCIATED PRIMARY BILIARY CIRRHOSIS?

Mario Garcia-Carrasco, Albert Pares, A Paula Vilas, Manuel Ramos-Casals, Victor Gil, M Eugenia Santos, Ricard Cervera, Josep Font, Miguel Ingelmo Barcelona, Spain and Puebla, Mexico

OBJECTIVE. To analyse the clinical significance of antimitochondrial antibodies (AMA) in patients with systemic autoimmune diseases (SAD). PATIENTS. We studied the epidemiologic, clinical and immunologic characteristics of patients with a defined SAD followed in our Unit, who tested positive for AMA. RESULTS. We found positive AMA in 25 patients: 14 with Sjogren’s syndrome (SS), 8 with cryoglobulinemia, 2 with systemic sclerosis and 1 with systemic lupus erythematosus. Of the 25 patients, 24 were female and one male, with a mean age of 62 years. We found liver involvement in 19 (76%) patients: hepatomegaly in 19, elevated transaminases in 14, elevated g -glutamyl transpeptidase in 17 and cholestasis in 9. Immunologic determinations showed antinuclear antibodies in 23, anti-parietal cell antibodies in 16, rheumatoid factor in 16, anti-smooth muscle ab in 13, elevated IgM levels in 11 and anti-Ro/SS-A in 10. Antibodies to hepatitis C virus (HCV) were detected in 12 patients. The AMA pattern was analyzed in 18 patients: 11 had a M2 pattern and 7 atypical patterns (M1, M5 or M6). The M2 pattern was observed more frequently in patients with SS (75 vs. 30%, p=0.04) and its presence was associated with liver involvement (83% vs. 17%, p=0.04). CONCLUSIONS. The systemic autoimmune disease most commonly associated with positive AMA was SS. Most patients with SAD and a AMA-M2 pattern showed some clinical or immunologic features of primary biliary cirrhosis (PBC), although no patient presented a defined PBC. The existence of positive AMA (M2 pattern) in patients with a previously known SAD could be the first sign of an incipient, associated PBC.

 

CLONAL B-CELL POPULATIONS IN THE BLOOD AND LIVER OF PATIENTS CHRONICALLY INFECTED BY THE HEPATITIS C VIRUS.

Laurent Vallat, Pascale Ghillani, Yves Benhamou, Vincent Thibault, Pierre Hausfater, Yvan Sterkers, Jean Charles Piette, Thierry Poynard, Helene Merle-Beral, Frederic Davi, Patrice Cacoub Paris, France

Numerous studies have suggested a possible role of the hepatitis C virus (HCV) in the development of B-cell lymphoproliferations. If the association of HCV with type II mixed cryoglobulinemia (CG) is well established, there is some discrepancy concerning its presence in B-cell lymphoma. High prevalences of HCV infection (up to 40%) have been reported in italian series, but have not been observed in other american and european studies, including two large french surveys.

Aim: To determine the frequency of circulating and liver infiltrating monoclonal B-cells in patients infected with HCV.

Patients and methods: 108 HCV-positive patients,(mean age 51 yrs), were prospectively studied. They had not received anti-HCV therapy for at least 6 months. CG were isolated and characterized by immunoblotting at 37°C (positive if = .05 g/l at least on 2 determinations). Clonality of B-cells was determined by DNA amplification of the heavy chain immunoglobulin gene (IgH) rearrangements followed by polyacrylamide gel electrophoresis (sensititivity=5%).

Results: A clonal B-cell population was detected in the blood of 20/108 (19%) patients. Among the 99 patients analyzed for the presence of CG, 34 were positive and 9/34 (26%) had a circulating clonal B-cell population. A clonal B-cell population was found in the blood of 9/22 (41%) patients with type II CG, but also in 8/65 (12%) patients without detectable CG. No clone was observed in the 12 patients with type III CG. For 69 patients, a liver biopsy was similarly analyzed: a clonal IgH rearrangement was detected in 12/14 (86%) cases having a clonal circulating population, and in 7/55 (13%) cases with polyclonal circulating B cells. Three of the 20 patients with a circulating clonal B-cell population developped a definite B-cell malignancy (Waldenstrom's macroglobulinemia = 2, marginal zone lymphoma = 1).

Conclusion Clonal B lymphocytes can frequently be detected in the blood and the liver of patients infected with HCV, in the absence of overt B-cell malignancy. These clones are usually, but not always, associated with the presence of type II CG. In rare patients, these clonal populations may evolve into a true B-cell neoplasia.

 

OVERLAP OF THE DIFFERENT ETIOLOGIC FACTORS ASSOCIATED WITH CRYOGLOBULINEMIA: ANALYSIS OF A SERIES OF 443 PATIENTS.

Mario Garcia-Carrasco, Olga Trejo, Manuel Ramos-Casals, Jordi Yagüe, Francisco Lopez, Alfonso Garcia-Carrasco, Ricard Cervera, Josep Font, Miguel Ingelmo Barcelona, Spain and Puebla, Mexico

OBJECTIVE. To study the main etiological factors associated with cryoglobulinemia in a universitary hospital, to determine the percentage of patients with no evidence of associated disease ("essential" cryoglobulinemia) and to analyze the amount of overlapping between the different etiologies.

PATIENTS. We analyzed 443 consecutive patients with cryoglobulinemia, who tested positive for circulating cryoglobulins in our Department of Immunology between 1991 and 1999. Of these 443 patients, 258 (58%) were women and 185 (42%) men (mean age 54 years, range 14 to 91).

RESULTS. Infectious diseases were detected in 331 (75%) patients, autoimmune diseases in 94 (24%), hematological disease in 33 (7%) and essential cryoglobulinemia in 49 (11%). Patients with autoimmune diseases showed a cryocrit higher than 5% (26%) more frequently compared with those with other etiologies (10%, p=0.003). HCV infection was found in 321 (73%) patients, HBsAg in 15 (3%) and HIV antibodies in 29 (7%). Forty (9%) patients had Sjogren’s syndrome (SS), 30 (7%) systemic lupus erythematosus (SLE), 7 (2%) periarteritis nodosa and 6 (2%) progressive systemic sclerosis. Finally, 16 (4%) patients had a NHL, 3 chronic lymphocytic leukemia, 3 multiple myeloma and 2 Hodgkin's lymphoma. When the overlapping of more than one etiological factor was analyzed, we found that most patients with HBsAg or HIV infection were also HCV positive. In addition, we observed a strong overlap between HCV and some autoimmune (50% in SS, 67% in PAN) or hematological (50% of NHL) diseases.

CONCLUSION. HCV infection was the main etiological factor identified, being present in 73% of patients with cryoglobulinemia. Of the systemic autoimmune diseases, SS and SLE were those more frequently associated to cryoglobulinemia, and NHL was the most frequent hematological process found. No associated disease was found in 11% of patients (essential cryoglobulinemia). Finally, we report a strong overlap between certain etiological factors (HCV, SS and NHL).