Life-Threatening Cryoglobulinemia: Clinical and Immunological Characterization of 29 Cases

doi:10.1016/j.semarthrit.2006.08.005

Seminars in Arthritis and Rheumatism

Volume 36, Issue 3, December 2006, Pages 189-196

https://doi.org/10.1016/j.semarthrit.2006.08.005 Get rights and content

Objectives

To analyze the etiology, clinical presentation, and outcomes of patients with life-threatening cryoglobulinemic vasculitis.

Methods

We studied 209 consecutive patients with cryoglobulinemic vasculitis. A potentially life-threatening cryoglobulinemia was considered as the development of renal failure, vasculitic abdominal involvement, pulmonary hemorrhage, or central nervous system involvement.

Results

Twenty-nine (14%) patients had life-threatening cryoglobulinemic vasculitis. There were 17 women and 12 men, with a mean age of 57 years. In 17 (59%) patients, life-threatening cryoglobulinemia was the initial clinical feature of the disease. The 29 patients had a total of 33 life-threatening episodes, which included renal failure due to cryoglobulinemic glomerulonephritis (n = 18), intestinal vasculitis (n = 8), pulmonary hemorrhage (n = 4), and central nervous system involvement (n = 3). In comparison with a control group of age–sex-matched patients with milder cryoglobulinemic vasculitis, those with severe cryoglobulinemic vasculitis had a higher frequency of fever (28% versus 7%, P = 0.017), type II cryoglobulins (100% versus 59%, P = 0.008), low C3 levels (55% versus 20%, P = 0.001), and a higher mean value of cryocrit (11.4% versus 3.3%, P = 0.004). Nineteen (66%) of the 29 patients with life-threatening involvement died, with the mortality rate reaching 100% in patients with intestinal ischemia and pulmonary hemorrhage.

Conclusion

Life-threatening cryoglobulinemic vasculitis was observed in 14% of our patients, with almost two-thirds of episodes occurring at the onset of the disease. Fever, high cryocrit levels, and low C3 levels were associated with this severe presentation. Two-thirds of the patients died, with mortality for pulmonary hemorrhage and intestinal ischemia reaching 100%.

Section snippets

Patient Selection

We studied 209 patients diagnosed with cryoglobulinemic vasculitis and consecutively followed in our hospital since 1991. Clinical and serological characteristics of all patients were collected on a protocol form, as previously described (12). We selected a control group of age–sex-matched patients without life-threatening vasculitic involvement to compare the following variables with respect to patients with life-threatening involvement: cryoglobulinemic manifestations (presence or absence of

General Characteristics

Twenty-nine (14%) of the 209 patients had life-threatening cryoglobulinemic vasculitis. There were 17 (59%) women and 12 (41%) men, with a mean age at diagnosis of severe involvement of 56.9 years (range, 25 to 87). In 17 (59%) patients, life-threatening involvement was the initial feature of cryoglobulinemia, while in the remaining 12 (41%) cases severe involvement was diagnosed after a mean time of 3.6 years (range 1 to 11) from the diagnosis of cryoglobulinemic vasculitis. Twenty-two

Discussion

Patients with cryoglobulinemia present a broad spectrum of clinical features. Although more than 50% of patients have a relatively benign clinical course with a good prognosis and survival (13), others have severe, life-threatening internal organ involvement. Why some cryoglobulinemic patients have severe cryoglobulinemic vasculitis remains unclear. Ferri and coworkers (13) recently found that 35% of their patients with cryoglobulinemic vasculitis had a moderate-to-severe clinical course, with

Acknowledgment

The authors thank David Buss for editorial assistance.

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Las crioglobulinas son inmunoglobulinas que precipitan in vitro a temperaturas inferiores a 37°C, cuya precipitación reversible tras la exposición a bajas temperaturas permite su detección en el laboratorio. Esta característica tan especial tiene también implicaciones patógenas, aunque los mecanismos moleculares involucrados no están totalmente dilucidados. La enfermedad asociada a las crioglobulinas es heterogénea, ya que no todos los pacientes la presentan, incluye diversas presentaciones sindrómicas (la vasculitis es la más frecuente, el síndrome de hiperviscosidad es excepcional), y puede asociarse a cuadros clínicos agudos de una elevada mortalidad. Hasta la aparición de los tratamientos específicos antivirales, la principal etiología ha sido la infección crónica por el virus hepatitis C (VHC), y en la actualidad se asocia principalmente a enfermedades autoinmunes sistémicas, neoplasias malignas y casos sin etiología identificada (crioglobulinemia esencial). El tratamiento debe ser modulado según la etiopatogenia predominante (vasculitis o hiperviscosidad), la gravedad de la afectación de órganos internos y, especialmente, la enfermedad subyacente asociada (viral, autoinmune o hematológica). Debido al complejo escenario etiológico, clínico y patológico de la crioglobulinemia, resulta esencial el reconocimiento temprano de las presentaciones clínicas más frecuentes, una evaluación clínica integral de los diferentes órganos que pueden verse afectados, y el trabajo multidisciplinar liderado desde una unidad especializada en enfermedades autoinmunes sistémicas.
Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures below 37 ̊C. Cryoglobulin-associated disease is heterogeneous, as not all patients present with it, includes various syndromic presentations (vasculitis is the most common, hyperviscosity syndrome is more exceptional), and can be associated with acute clinical pictures with high mortality. Until the appearance of specific antiviral treatments, the main aetiology has been chronic HCV infection, and currently it is mainly associated with systemic autoimmune diseases, malignant neoplasms and cases with no identified aetiology (essential cryoglobulinemia). Treatment should be modulated according to the predominant etiopathogenesis (vasculitis or hyperviscosity), the severity of internal organ involvement and, especially, the associated underlying disease. Due to the complex aetiological, clinical and pathological scenario of cryoglobulinaemia, early recognition of the most common clinical presentations, a comprehensive clinical assessment of the different organs that may be affected, and multidisciplinary work led by a unit specialised in systemic autoimmune diseases is essential.
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Citation Excerpt :
Cryoglobulinemic vasculitis (CV) is a serious chronic disease whose typical manifestations are lower limb purpura, asthenia and arthralgia, (the so-called triad of Meltzer and Franklin) [1], peripheral neuropathy, lower limb ulcers, Raynaud’s phenomenon, sicca syndrome and mesangio-proliferative glomerulonephritis [2–4]. Life-threatening conditions such as hyperviscosity syndrome, rapidly progressive renal failure due to massive intra-tubular immunocomplex (IC) precipitation, and extended necrosis due to small vessel IC precipitation have also been described [5,6], as has a “catastrophic-like” multi-system syndrome [3,4,7–9]. The disease is caused by the proliferation of B lymphocyte clones that produce a rheumatoid-like factor [10], which is generally an IgM that binds IgG of different idiotype specificity to form ICs known as mixed cryoglobulins (MCGs), which can precipitate at temperatures of <37 °C [11].
To assess the effectiveness of apheresis therapy (AT) in treating the clinical manifestations of patients with complicated cryoglobulinemic vasculitis (CV).
A retrospective cohort study of 159 CV patients attending 22 Italian Centers who underwent at least one AT session between 2005 and 2015. The response to AT was evaluated on the basis of a defined grading system.
Peripheral neuropathy was the most frequent clinical condition leading to AT. Therapeutic plasma exchange was used in 70.4% of cases. The outcome of AT was rated very good in 19 cases, good in 64, partial/transient in 40, and absent/not assessable in 36. Life-threatening CV-related emergencies and renal impairment independently correlated with failure to respond to AT. The independent variables associated with an increased risk of death were age at the time of the first AT session, multi-organ life-threatening CV, the presence of renal impairment and failure to respond to AT. The time-dependent probability of surviving until CV-related death in the second year was 84%, with an AHR in patients with absent/not assessable response to AT of 11.25.
In this study AT is confirmed to be a safe procedure in patients with CV. Early AT should be considered in patients with severe CV, especially in cases with impending renal involvement, in order to prevent irreversible kidney damage. Although its efficacy in patients with multi-organ failure is limited, AT is the only treatment that can rapidly remove circulating cryoglobulins, and should be considered an emergency treatment.

View all citing articles on Scopus

: This work was supported by Grant FIS 04/0701.

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Life-Threatening Cryoglobulinemia: Clinical and Immunological Characterization of 29 Cases

Objectives

Methods

Results

Conclusion

Section snippets

Patient Selection

General Characteristics

Discussion

Acknowledgment

Lancet Infect Dis

Am J Med

Semin Arthritis Rheum

Am J Med

Kidney Int

Am J Gastroenterol

Am J Med

Am J Med Sci

Am J Med Sci

Am J Med Sci

Mayo Clin Proc

Am J Kidney Dis

Cryoglobulinemic vasculitis

Arthritis Rheum

Cryoglobulins

J Clin Pathol

Mixed cryoglobulinemia: new concepts

Lupus

Mixed cryoglobulinemia cross-reactive idiotypes: implications for the relationship of MC to rheumatic and lymphoproliferative diseases

Semin Hematol

Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia

Arthritis Rheum

A role for hepatitis C virus infection in type II cryoglobulinemia

N Engl J Med

Extrahepatic manifestations in patients with chronic hepatitis C virus infection

Curr Opin Rheumatol

Clonality of B-cells in portal lymphoid infiltrates of HCV-infected livers

J Pathol

Clonal analysis of intrahepatic B cells from HCV infected patients with and without mixed cryoglobulinemia

J Immunol

Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center

Medicine (Baltimore)

Long term course of mixed cryoglobulinemia in patients infected with hepatitis C virus

J Rheumatol