Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients

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Abstract

Background

Mixed cryoglobulinemia (MC) is a systemic vasculitis secondary to circulating immune complex deposition in the small vessels. In the overwhelming majority of patients, hepatitis C virus (HCV) infection represents the triggering factor of the disease. MC is characterized by multiple organ involvement, mainly skin, liver, renal, peripheral nerves, and less frequently by widespread vasculitis and cancer.

Objectives

To investigate the demographic, clinical, serologic features, and survival in a large series of MC patients.

Methods

The study included 231 MC patients recruited between 1972 and 2001 at the Rheumatology Unit of the University of Pisa. All patients underwent wide clinicoserologic and virologic assessment. Cumulative survival rates were computed by the Kaplan-Meier method; moreover, the prognostic relevance of the main variables was investigated by Cox model analysis.

Results

In 92% of cases, the presence of HCV infection was demonstrated (anti-HCV antibody, 92%; HCV RNA, 90%), whereas hepatitis B virus (HBV) represented the possible causative agent in only 1.8% of patients (HBV DNA). Clinically, the MC syndrome followed a relatively benign clinical course in over 50% of cases, whereas a moderate-severe clinical course was observed in one third of patients whose prognosis was severely affected by renal and/or liver failure. In a limited, but significant, percentage (15%) of individuals, the disease was complicated by a malignancy, ie, B-cell lymphoma, and less frequently by hepatocellular carcinoma, or thyroid cancer. The survival study by the Kaplan-Meier method revealed a significantly lower cumulative 10th-year survival, calculated from time of diagnosis, in MC patients compared with expected death in the age- and sex-matched general population. Moreover, significantly lower survival rates were observed in males and in subjects with renal involvement. The multivariate analysis by the Cox proportional hazard regression model further supported the above findings: an increased mortality risk of 98% was observed for male gender (male/female hazard ratio, 1.978) and of 197% in patients with, compared with those without, renal involvement (hazard ratio, 2.967). At the end of the follow-up, 97 patients were deceased, and in 79of 97 patients, the causes of death were ascertained: nephropathy (33%), malignancies (23%), liver involvement (13%), and diffuse vasculitis (13%) were the most frequent causes of death.

Conclusions

Careful patient monitoring is recommended for a timely diagnosis of life-threatening MC complications, mainly nephropathy, widespread vasculitis, and B-cell lymphoma or other malignancies.

Section snippets

Methods

The study population (231 patients; 174 females, 57 males) was recruited between 1972 and 2001 from the Rheumatology Unit of the University of Pisa, Medical School (Table 4). At the time of diagnosis, all patients showed clinicoserologic and pathologic features sufficient for a diagnosis of definite MC according to preliminary classification criteria (16) (Table 3).

Clinical assessment was performed on the basis of 2 main categories: demographic data and clinical features observed at the time

Results

Demographic, clinicoserologic, and virologic features of MC patients at the beginning and at the end of the follow-up are summarized in Table 4. The patient mean age at the beginning of the follow-up was 56.4 ± 11.2 (SD) years. At the end of the study, 21 patients (9.1%) were lost to follow-up. During 2001, the vital status of the remaining 210 patients was ascertained: 113 of 210 (54%) were still alive, whereas 97 of 210 (46%) were deceased after 12.3 ± 7.6 (mean ± SD) years from disease

Discussion

The present study evaluated the prognostic value of epidemiologic and clinicoserologic parameters and survival in a large series of patients with MC. Renal failure caused by chronic glomerulonephritis was responsible for death in one third of deceased patients; chronic hepatitis with cirrhosis, widespread vasculitis, and B-cell non-Hodgkin’s lymphoma were other important causes of death. The cumulative 10-year survival calculated by the Kaplan-Meier method showed a significantly lower rate in

Clodoveo Ferri, MD: Professor of Rheumatology, Department of Internal Medicine, University of Pisa, Medical School, Pisa, Italy

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    • Cited by (0)

    Clodoveo Ferri, MD: Professor of Rheumatology, Department of Internal Medicine, University of Pisa, Medical School, Pisa, Italy

    Marco Sebastiani, MD: Fellow of Rheumatology, Department of Internal Medicine, University of Pisa, Medical School, Pisa, Italy

    Dilia Giuggioli, MD: Assistant Professor, Department of Internal Medicine, University of Pisa, Medical School, Pisa, Italy

    Massimimiliano Cazzato, MD: Assistant Professor, Department of Internal Medicine, University of Pisa, Medical School, Pisa, Italy

    Giovanni Longombardo, BS: Investigator, Department of Internal Medicine, University of Pisa, Medical School, Pisa, Italy

    Alessandro Antonelli, MD: Investigator, Department of Internal Medicine, University of Pisa, Medical School, Pisa, Italy

    Rodolfo Puccini, MD: Assistant Professor, Division of Nephrology, S. Chiara Hospital, Pisa, Italy

    Claudio Michelassi, BS: Investigator, Clinical Physiology, CNR Pisa, Italy

    Anna Linda Zignego, MD: Associate Professor of Internal Medicine, Department of Internal Medicine, University of Florence, Medical School, Florence, Italy.

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