Download Cryoglobulinemic vasculitis

Cryoglobulinemic vasculitis
Clodoveo Ferri and Maria Teresa Mascia
Purpose of review
Cryoglobulinemic vasculitis is an immune-complexmediated systemic vasculitis involving small–medium-sized
vessels. A causative role of hepatitis C virus in over 80%
patients has been definitively established, with
heterogeneous geographical distribution. This review
focuses on recent etiopathogenetic, clinico-diagnostic, and
therapeutical studies.
Recent findings
Hepatitis C virus cannot be integrated into the host
genome; it may exert a chronic stimulus to the immune
system. The interaction between hepatitis C virus envelope
protein E2 with B-cell CD81 receptor may increase the
frequency of VDJ rearrangement in antigen-reactive B
lymphocytes. One consequence is the activation of various
protooncogenes, including antiapoptotic Bcl-2. The
extended B-cell survival is responsible for autoantibody and
immune-complex production, including mixed
cryoglobulins; some malignancies, mainly B-cell
lymphomas, may complicate cryoglobulinemic vasculitis.
Environmental or viral/host genetic cofactors should be
relevant in the pathogenesis of hepatitis C virus-related
diseases. Cryoglobulinemic vasculitis may overlap with
other diseases (systemic vasculitides, Sjögren’s syndrome,
autoimmune hepatitis, lymphoma), which should be
carefully considered for a correct diagnosis and treatment.
Cumulative survival of cryoglobulinemic vasculitis is
significantly lower compared with the general population.
Therapeutic strategies for cryoglobulinemic vasculitis
include etiologic (antiviral), pathogenetic (cyclophosfamide,
rituximab), or symptomatic (steroids, plasmapheresis)
treatments, which should be tailored to the individual patient
according to the severity/activity of clinical symptoms.
Summary
Cryoglobulinemic vasculitis represents a crossroads
among autoimmune and lymphoproliferative disorders; as
hepatitis C virus infection is the major causative factor,
cryoglobulinemic vasculitis is an important model for
etiopathogenetic studies of virus-related diseases.
Keywords
cryoglobulinemic vasculitis, hepatitis C virus, lymphoma,
mixed cryoglobulinemia, Sjögren’s syndrome
Curr Opin Rheumatol 18:54–63. ß 2006 Lippincott Williams & Wilkins.
Chair and Rheumatology Unit, Department of Internal Medicine, University of
Modena e Reggio Emilia, Medical School, Modena, Italy
Correspondence to Professor Clodoveo Ferri MD, Reumatologia, Università di
Modena e Reggio Emilia, Policlinico di Modena, Via del Pozzo, 71, 41100 Modena,
Italy
Tel: +39 059 4222279; fax: +39 059 4223260; email: [email protected]
Current Opinion in Rheumatology 2006, 18:54–63
54
Abbreviations
HBV
HCV
hepatitis B virus
hepatitis C virus
ß 2006 Lippincott Williams & Wilkins
1040-8711
Introduction
Cryoglobulinemia is defined as the presence of circulating immunoglobulins that precipitate at temperatures
below 378C and redissolve on re-warming [1–5]. According to cryoprecipitate composition [2], cryoglobulinemia
is classified into three serological subsets: monoclonal
cryoimmunoglobulinemia (type I) composed of single
monoclonal immunoglobulin, mixed cryoglobulinemia
containing a mixture of polyclonal IgG and mono (type
II) or polyclonal (type III) IgM rheumatoid factor. Type I
cryoglobulinemia, frequently associated with well known
hematological disorders, is usually asymptomatic per se
[2–5].
Both type II and III mixed cryoglobulinemia can be
classified as essential or secondary in the absence/presence of other well defined infectious, immunological or
neoplastic diseases [1–7]. Essential mixed cryoglobulinemia is traditionally classified among systemic vasculitis
[1–7]. During the last 15 years there has been an increasing interest in cryoglobulinemic vasculitis due to its
striking association with hepatitis C virus (HCV); this
association represents one of the most promising models
of virus-induced autoimmune-lymphoproliferative disorders [5–7]. This review analyzes the recent clinicopathogenetic studies and therapeutic strategies of cryoglobulinemic vasculitis.
Cryoglobulinemic vasculitis
The so-called ‘essential’ mixed cryoglobulinemia is
characterized by a typical clinical triad – purpura, weakness, arthralgias – and multisystem organ involvement
[1–7]. The pathological hallmark of mixed cryoglobulinemia is a leucocytoclastic vasculitis of small and medium-sized vessels, due to the deposition of circulating
immune complexes and complement, and is responsible
for cutaneous and visceral organ involvement (Fig. 1)
[1–10]. In the presence of the above clinico-serological
and pathological alterations, the terms mixed cryoglobulinemia and cryoglobulinemic vasculitis refer to the same
clinical syndrome.
Cryoglobulinemic vasculitis Ferri and Mascia 55
Figure 1 Leukocytoclastic vasculitis and organ involvement
Cryo/noncryoprecipitable immune complexes
(IgG-IgM RF,complement, HCV-LDL/VLDL)
of hepatotropic viruses in cryoglobulinemic vasculitis
has long been hypothesized [12,13]. Hepatitis B virus
(HBV) represents an etiological factor of cryoglobulinemic vasculitis in a minority of individuals (Table 2)
[5,11].
Hepatitis C virus-related cryoglobulinemic vasculitis
Leukocytoclastic vasculitis
(arterioles, capillaries, venules)
Skin/
diffuse
vasculitis
Nephritis
peripheral
neuropathy
Endocrine
disorders
Leukocytoclastic vasculitis is the pathological hallmark of cryoglobulinemic vasculitis, responsible for various skin disorders and visceral
organ involvement. It is due to small vessel deposition of circulating
immune complexes, complement, with coparticipation of hepatitis C
virus (HCV) particles and low/very-low-density lipoprotein receptors
(LDL, VLDL). RF, rheumatoid factor.
Definition/classification of
cryoglobulinemic vasculitis
There are no available classification/diagnostic criteria for
cryoglobulinemic vasculitis. Table 1 shows the preliminary criteria proposed for cryoglobulinemic vasculitis
classification [5,11]. In clinical practice, the main diagnostic parameters are serum mixed cryoglobulins with
rheumatoid factor activity, low C4, orthostatic skin purpura, and leukocytoclastic vasculitis. Diagnostic features
may also include the involvement of one or more organs,
as well as clonal B-lymphocyte expansion, which
represents the underlying immune-system alteration of
the disease [5–7,9,10,11].
Etiopathogenesis of
cryoglobulinemic vasculitis
Given the frequent association between cryoglobulinemic vasculitis and liver involvement, a causative role
Following the identification of HCV [14], this agent has
been suspected to play a role in cryoglobulinemic vasculitis [15]. A high prevalence (86%) of HCV viremia was
demonstrated in a large series of cryoglobulinemic vasculitis patients [15]. The causative role of HCV infection
in cryoglobulinemic vasculitis has been definitively
established on the basis of epidemiological, pathological,
and laboratory investigations [5–7,9,10,11,15,16]. As
the main triggering factor of mixed cryoglobulinemia
syndrome is HCV, the term ‘essential’ is no longer
appropriate in almost three-quarters of patients [5,11].
HCV has been recognized as both a hepato and lymphotropic virus [5,6,17]. The infection of lymphoid tissue
may trigger a constellation of autoimmune and lymphoproliferative disorders in chronically HCV-infected individuals [5–7,9,10,11,16,18 –20].
Circulating mixed cryoglobulins are frequently detectable in HCV-infected individuals (40–50%), whereas
overt cryoglobulinemic vasculitis develops in only a
minority of cases (<5%) [5,18,21–23]. There is a geographical heterogeneity in the prevalence of HCVrelated cryoglobulinemic vasculitis: this association is
particularly frequent in southern Europe and rare in
northern Europe, northern America, and other countries
[5,24–26]. Given the quite homogeneous diffusion of
HCV infection worldwide, the involvement of particular
viral/host genotypes, environmental or host genetic
factors should contribute to the pathogenesis of cryoglobulinemic vasculitis, as well as other autoimmunelymphoproliferative disorders (Figs 2 and 3) [5,6,9,27–
29,30,31,32,33,34].
Table 1 Proposed criteria for the classification of mixed cryoglobulinaemia patients
Criteria
Serological
Pathological
Clinical
Major
Mixed cryoglobulins
Low C4
Rheumatoid factorþ
HCVþ
HBVþ
Leukocytoclastic
Vasculitis
Clonal B-cell infiltrates
(liver and/or bone marrow)
Purpura
Minor
Chronic hepatitis
MPGN
Peripheral neuropathy
Skin ulcers
‘Definite’ mixed cryoglobulinemia syndrome
Serum mixed cryoglobulins (low C4) þ purpura þ leukocytoclastic vasculitis
Serum mixed cryoglobulins (low C4) þ two minor clinical symptoms þ two minor serological/pathological findings
‘Essential’ or ‘secondary’ mixed cryoglobulinemia
Absence or presence of well known disorders (infectious, immunological or neoplastic)
HCVþ or HBVþ, markers of hepatitis C virus or hepatitis B virus infection (anti-HCV HCV RNA; HBV DNA or HBsAg); MPGN, membranoproliferative glomerulonephritis.
56 Vasculitis syndromes
Table 2 Clinico-epidemiological and serological features of 231
cryoglobulinemic vasculitis patients
Female/male ratio
Mean age at diagnosis (years)
Mean disease duration (years)
Purpura
Weakness
Arthralgias
Arthritis
Raynaud’s phenomenon
Sicca syndrome
Skin ulcers
Peripheral neuropathy
Liver involvement
Renal involvement
Lung involvement
Diffuse vasculitis
Hyperviscosity syndrome
B-cell lymphoma
Hepatocellular carcinoma
Thyroid cancer
MC type II/type III ratio
Cryocrit %
Rheumatoid factor
C4 mg% (nv 20–60)
C3 mg% (nv 90–180)
Autoantibodies
anti-HCV Ab RNA
anti-HBV Ab
HBsAg
3
56.4 11.2
10.5 7.3
98%
100%
98%
6.7%
48%
53%
22%
80%
77%
30%
1.9%
6.2%
0.5%
10%
3.3%
1%
1.7
4.4 11.7
98%
11 7.7
100 28
56%
92%
42%
9%
Autoantibodies: ANA and/or ENA and/or AMA and/or ASMA (see text);
MC: mixed cryoglobulinemia.
In addition, HCV is a positive, single-stranded RNA virus
without a DNA intermediate in its replicative cycle, so
that viral genomic sequences cannot be integrated into
the host genome. The above considerations suggest that
HCV per se might be insufficient to drive the different
autoimmune-lymphoproliferative disorders observed in
infected individuals. It has been hypothesized that HCV
infection exerts a chronic stimulus to the immune system,
which facilitates the clonal B-lymphocyte expansion
[5,6]. The molecular mimicry mechanism involving
Figure 2 The pathogenesis of cryoglobulinemic vasculitis
Cryoglobulinemic vasculitis: pathogenetic factors
HCV
- genotypes (2a/c?)
- HCV proteins:
E2
core
NS3
NS4
NS5A
Host
- autoantigens
- CD81
- LDLreceptors
- HLA antigens
- sex hormones
Unknown environmental factors
The pathogenesis of cryoglobulinemic vasculitis may include particular
hepatitis C virus (HCV) genotypes and proteins, host factors, and
possibly other unknown environmental agents (see text).
Figure 3 Relationship between hepatitis C virus infection (HCV)
and immune-system alterations responsible for cryoglobulinemic vasculitis and other autoimmune or neoplastic disorders
Genetic and/or environmental factors
HCV infection
HCV-E2
CD81
LYMPHOCYTES
T(14; 18) translocation
Viral antigens
Autoantigens
Molecular
mimacry
Autoreactive cytotoxic T cells
Bcl2 activation
Benign B-cell expansion
Autoantibodies, RF, CIC
cryoglobulins
IMMUNOLOGICAL DISORDERS:
arthritis, porphyria c.t., sicca s.
thyroiditis, gonadal dis., diabetes,
hepatitis, glomerulonephritis,
lung fibrosis, etc.
Inhibition of apoptosis
Prolonged B-cell survival
Other genetic aberrations
(c-myc, Bcl6, p53, etc.)
Cryoglobulinemic
vasculitis
B-cell lymphomas
Hepatocellular carcinoma
Thyroid cancer
HCV infection may exert a chronic stimulus on the immune system; in
particular, various pathogenetic mechanisms can be taken into account:
interaction between HCV envelope protein E2 and CD81 on both
hepatocytes and lymphocytes; a molecular mimicry mechanism involving
HCV antigens and host autoantigens; and T(14;18) translocation commonly found in HCV-infected individuals, particularly in cryoglobulinemic
vasculitis patients; the consequent activation of Bcl2 proto-oncogene
may lead to prolonged B-cell survival. The ‘benign’ B-lymphocyte expansion may be responsible for the production of various autoantibodies,
including rheumatoid factor and cryo and noncryoprecipitable immune
complexes (CICs). Consequently, various autoimmune (organ and nonorgan specific) disorders and cryoglobulinemic vasculitis may develop.
The indolent B-cell proliferation underlying mixed cryoglobulinaemia may
be complicated by frank malignant lymphoma in about 10% of patients.
Prolonged B-cell survival may predispose to activation of other protooncogenes, which ultimately may lead to malignancies. There is a clinicoserologic and pathologic overlap among different HCV-related diseases;
cryoglobulinemic vasculitis represents a crossroads between these
autoimmune and neoplastic disorders. RF, rheumatoid factor; porphyria
c.t., porphyria cutanea tarda.
particular HCV antigens, such as NS5A and HCV core
proteins [35,36], and host autoantigens can be involved in
B-lymphocyte activation and autoantibody production
(Fig. 2) [5].
Moreover, a significant percentage of peripheral blood
lymphocytes in HCV-infected individuals, particularly
cryoglobulinemic vasculitis with type II mixed cryoglobulinemia, show a t(14;18) translocation, responsible for
Bcl-2 activation [5,11,37]. This proto-oncogene leads to
extended B-cell survival by inhibiting the apoptosis
[5,37]; consequently, B-lymphocyte expansion is responsible for a wide autoantibody production [5,6,18,21,
22,24]. Besides, HCV envelop protein E2 is able to bind
the CD81 molecule expressed on both hepatocytes and B
lymphocytes [38]; CD81 is a cell-surface protein that, on
B cells, is part of a complex with CD21, CD19, and Leu
13. This complex reduces the threshold for B-cell
Cryoglobulinemic vasculitis Ferri and Mascia 57
activation; the interaction with HCV-E2 might increase
the frequency of VDJ rearrangement in antigen-reactive
B cells. One possible consequence could be the production of important genetic aberrations observed in
HCV-infected individuals, leading in some cases to overt
malignancy (Figs. 2 and 3) [5,6,11,37,39,40,41,
42,43].
Nonhepatitis C virus-related cryoglobulinemic vasculitis
According to the above-mentioned geographical heterogeneous distribution of HCV-related cryoglobulinemic
vasculitis, patients with HCV-negative cryoglobulinemic
vasculitis are commonly found in some areas such as
northern Europe [25] where the overall prevalence of
the disease is significantly lower compared with the
Mediterranean area [5,18,21,44]. A wide number of other
infectious agents may be associated with cryoglobulinemia, often as anecdotal observations without a particular
clinical relevance [3,45–49]. Trejo et al. [50] evaluated
the clinical relevance of mixed cryoglobulinemia and its
relationship with other systemic disorders. Among 57
patients with mixed cryoglobulinemia, HCV infection
was detected in 82%, while ‘essential’ mixed cryoglobulinemia was present in 7%; the remaining cases were
associated with other infections or well known connective
tissue diseases. We also analyzed retrospectively 195
patients with mixed cryoglobulinemia typified during
1 year at the laboratory of our hospital (M.T. Mascia,
personal communication). Only 31/195 (16%) patients
were HCV-negative; clinically, they showed a connective
tissue disease in 18/31 (58%), ‘essential’ mixed cryoglobulinemia in 9/31 (29%), malignancy in 2/31 ((6%), and
other infections in 2/31 (6%). The overall evaluation of
our patients with HCV-negative mixed cryoglobulinemia
suggest the following considerations: ‘essential’ mixed
cryoglobulinemia is particularly rare and often manifests
as incomplete cryoglobulinemic vasculitis syndrome; in
patients with well known connective tissue disease there
are only trace amounts of cryoglobulins, without typical
cryoglobulinemic vasculitis syndrome, whereas high
cryocrit levels were invariably associated with HCV
infection; patients with Sjögren’s syndrome showed
higher levels of cryocrit along with cryoglobulinemic
vasculitis syndrome, making it indistinguishable from
that observed in HCV-positive patients.
In HCV-negative cryoglobulinemic vasculitis patients an
occult HCV infection should be taken into account [51],
as observed in patients with persistently abnormal liver
function tests of unknown etiology [52]. A liver biopsy
[53] or bone marrow biopsy and long-term virological
follow-up [51] may be necessary for a correct assessment.
The actual prevalence of occult HCV infection in cryoglobulinemic vasculitis patients should be investigated
further due to its pathogenetic and therapeutic implications.
Clinical manifestations
The prevalence of single cryoglobulinemic vasculitis
manifestations may vary among patient series from different referral centres [5,6]. Table 2 shows the main demographic, clinico-serological, and virological features
observed in a large Italian cryoglobulinemic vasculitis
patient series [11], which is quite comparable to other
reported series [5,9]. Cutaneous manifestations and
arthralgias or arthritis are the most frequent symptoms
[5,11,54,55]. Almost half of patients complained of
xerostomia and xerophthalmia, but only few met the
current criteria for the classification of primary Sjögren’s
syndrome [5,11].
Peripheral neuropathy is a frequent complication of
cryoglobulinemic vasculitis, usually as mild sensory
neuritis [5,11,56]. Sensory-motor neuropathy may
appear abruptly, often as mononeuritis [5,11]. Central
nervous system involvement with dysarthria and hemiplegia is rare and often difficult to distinguish from the
most common atherosclerotic manifestations [5,11,
57,58].
Chronic hepatitis commonly shows a mild–moderate
clinical course; it may evolve to cirrhosis in a quarter
of cases and it is rarely complicated by hepatocellular
carcinoma [5,11]. Membranoproliferative glomerulonephritis type I is one of the most important conditions
[5,11,59] (Table 2).By contrast, multiple organ involvement secondary to widespread vasculitis is observed in
a minority of patients [3,5,7,9,11]. Interstitial lung
fibrosis has been anecdotally observed in HCV-positive
patients with or without cryoglobulinemic vasculitis syndrome; more often it is characterized by subclinical
alveolitis [5,11]. Various endocrine gland dysfunctions
can be observed in a significantly higher number of
cryoglobulinemic vasculitis patients compared with age
and sex-matched controls; in particular, diabetes type II,
thyroid, and gonadal dysfunction [5,11,40,60,61].
Hyperviscosity syndrome due to high levels of cryoglobulins is rare [5]. Reduced hemolytic complement
activity, with typical pattern of low or undetectable
C4, is very frequently found; however, complement
levels and cryocrit rarely correlate with the severity of
cryoglobulinemic vasculitis [5,9,11].
B-NHL represents the most frequent neoplastic complication of cryoglobulinemic vasculitis [4,6,11,62,63,
64], while hepatocellular carcinoma and papillary thyroid cancer are less frequently observed (Fig. 3) [5,6,
11,40].
Different serum autoantibodies can be detected in over
half of cryoglobulinemic vasculitis patients [5,11,65,66].
Both anti-HCV antibodies and HCV viremia are detectable in the large majority of mixed cryoglobulinemia
58 Vasculitis syndromes
Figure 4 Overlap between primary Sjögren’s syndrome (SS)
and cryoglobulinemic vasculitis (CV)
HCV - Cryo. vasculitis - Sjögren’s S
HCV
CV
3
2
1
Primary
SS
Cryoglobulinemic vasculitis vs primary Sjögren’s S
Similarities
Age,sex
Sicca syndrome,
Arthralgias, arthritis
RF+, cryoglobulins
Lymphoma
Differences
Hepatitis, glomerulonephritis
Skin and salivary gland
histology Ab anti-SSA/SSB
Low complement
HCV infection
Primary Sjögren’s syndrome (SS) and cryoglobulinemic vasculitis (CV)
may share some important clinico-serological features. However, the
severity of istopathological pattern of salivary gland involvement and
specific autoantibodies (anti-RoSSA/LaSSB) are rarely found in CV
patients; conversely, cutaneous leukocytoclastic vasculitis, and visceral
organ involvement (renal, liver), low C4, and HCV infection are seldom
recorded in primary SS. The figure reproduces the possible overlapping
of these two disorders. There is a continuum from the classical CV to
primary SS, which may include (1) Primary SS with HCV-negative
cryoglobulinemic vasculitis; (2) HCV-associated SS without cryoglobulinemic vasculitis; and (3) Overlap syndrome SS/cryoglobulinemic vasculitis in HCV-positive patients; due to its clinico-therapeutical
implications this phenotype could be better classified as cryoglobulinemic vasculitis. RF, rheumatoid factor.
patients, associated in some individuals to HBV markers,
while ongoing HBV infection is rare [5,11,15].
Overlapping disorders
Given its clinical polymorphism, mixed cryoglobulinemia
syndrome may overlap with a variety of immunological
and neoplastic diseases; in particular, other systemic
vasculitides, Sjögren’s syndrome, autoimmune hepatitis,
and B-cell lymphoproliferative disorders (Fig. 3).
Differential diagnosis with other systemic vasculitides is
quite easy if clinico-serological and histopathological
features are correctly evaluated. Sjögren’s syndrome
and cryoglobulinemic vasculitis may share various symptoms (Fig. 4) [67,68]. In large series of patients with
Sjögren’s syndrome, the presence of mixed cryoglobulinemia is around 20% [69,70]; the presence of cryoglobulinemia seems to identify a particular clinical subset
of Sjögren’s syndrome, characterized by a poor prognosis
due to more severe internal organ involvement and
frequent evolution to malignant lymphomas [69,70,
71,72]. Careful patient clinical assessment is often sufficient for a correct diagnosis in the majority of cases
(Fig. 4). In some patients, however, a differential diagnosis may be very difficult; therefore, it may be necessary
to classify these cases as cryoglobulinemic vasculitis
Sjögren’s overlap syndrome [5,11,67].
An intriguing but controversial aspect is the possible
etiopathogenetic role of HCV in Sjögren’s syndrome
[73], suggested by the well known HCV sialotropism
and by a recent clinico-epidemiological study focusing
on patients with HCV-associated Sjögren’s syndrome
[74]. Interestingly, these patients show a significant
low rate of anti-RoSSA/LaSSB (23%) along with a high
prevalence of mixed cryoglobulinemia (50%), hypocomplementemia (51%), and systemic vasculitic manifestations (58%). The authors suggest that this particular
condition cannot be classified as primary Sjögren’s syndrome [74]; in fact, at least 50% of these patients could
be better classified as having typical cryoglobulinemic
vasculitis syndrome. It is not surprising that, in genetically predisposed individuals, the complex immune-system alterations triggered by HCV chronic infection may
produce particular phenotypes, which may meet the
diagnostic criteria of well known diseases, including
Sjögren’s syndrome, systemic lupus, rheumatoid arthritis,
and so on [5,11,18,19,54,75,76].
Patients with autoimmune hepatitis may present mixed
cryoglobulins, HCV infection, and extrahepatic manifestations such as thyroiditis, sicca syndrome, or arthritis
[65]. In these instances, some patognomonic findings,
including high titre of specific autoantibodies (ANA,
ASMA, anti-LKM1) for autoimmune hepatitis, or symptoms such as membranoproliferative glomerulonephritis
or leukocytoclastic vasculitis for cryoglobulinemic vasculitis, may be useful for the differential diagnosis [11].
Finally, B-NHL complicating HCV-related cryoglobulinemic vasculitis can be confused with ‘idiopathic’
B-NHL producing clinico-serological findings of cryoglobulinemic vasculitis (Fig. 3). The differential diagnosis of
these two entities may be important, especially for its
therapeutic implications: the treatment of B-cell NHL
complicating the cryoglobulinemic vasculitis may need
some precautions due the concomitance of HCV infection with possible liver or renal failure [11].
Prognosis
Few clinico-prognostic studies are available in the literature [11,77,78]. The cumulative 10th year survival of
mixed cryoglobulinemia patients is significantly lower
compared with the age and sex-matched general population [11]. The worse prognostic factors are the
patient’s age at the time of diagnosis (>60 years), male
gender, and renal involvement; however, death is often
Cryoglobulinemic vasculitis Ferri and Mascia 59
Figure 5 Etiopathogenetic process of hepatitis C virus (HCV)related cryoglobulinemic vasculitis (CV) and therapeutic interventions
the result of concomitant, severe clinical manifestations
[11].
Treatment
HCV infection
HCV eradication
Interferon-a + ribavirin
Benign B-cell expansion
Immunosuppressors
autoantibodies CIC, and
autoantibodies,
production
cryoglobulin productio
Cyclophosphamide, rituximab
The treatment of cryoglobulinemic vasculitis is particularly challenging because of its complex etiopathogenesis, including HCV infection, autoimmune, and
lymphoproliferative alterations. We can treat the disease
at different levels by means of etiological, pathogenetic,
or symptomatic therapies (Figs 5 and 6) [5,6, 11,79].
CIC reduction
Plasma exchange, LAC-diet
Cryoglobulinemic
vasculitis
Steroids
B-cell lymphoma
Chemotherapy
Cryoglobulinemic vasculitis is the result of three main clinico-pathological alterations: chronic HCV infection, B-lymphocyte proliferation, and
immune-complex-mediated vasculitis. Following the cascade of events
leading from HCV infection to overt cryoglobulinemic vasculitis, we can
treat the disease at different levels by means of etiologic, pathogenetic,
and symptomatic often combined therapies (see text). CIC, circulating
immune complex; LAC-diet, low-antigen-content diet.
Etiological treatment
An attempt at HCV eradication should be done in all
cases of HCV-associated cryoglobulinemic vasculitis:
antiviral therapy may improve the immune-lymphoproliferative disorder underlying the disease [80,81], while
combined a-interferon and ribavirin might achieve the
eradication of HCV infection in a significant number of
treated patients [79,82,83,84]. Controlled clinical
trials are necessary, however, to definitively evaluate
the effect of antiviral therapy in HCV-related cryoglobulinemic vasculitis. In the absence of HCV eradication,
its usefulness is often transient and seldom associated
with re-exacerbation or appearance of important complications, including vasculitic manifestations, peripheral
sensory-motor neuropathy, rheumatoid-like polyarthritis,
Figure 6 Therapeutic strategies of cryoglobulinemic vasculitis
Therapeutic strategies of cryoglobulinemic vasculitis
Asymptomatic
Mild–moderate
Purp.,weak.,arthr.
mild neuropathy
Moderate–severe
active CH, MPGN
skin vasculitis
Severe, rapidly
progressive
glomerulonephritis
sensory-motor
neuropathy
widespread vasculitis
monitoring
low–medium dose CS
± LAC-diet
± other symptomatics
peg-IFN+ Riba???
Possible sequential treatment
Severe-active manifestations:
nephritis, skin ulcers,
sensory-motor neuropathy,
widespread vasculitis,
B-lymphomas, etc.
Rituximab
IFN+RIBA
peg-IFN+ Riba
Plasma exchange
+ CS + CFX
or Rituximab
Active chronic hepatitis,
minor CV manifestations
IFN+RIBA
Rituximab
Left: therapeutic strategies of HCV-related cryoglobulinemic vasculitis: the therapeutic interventions should be decided on the basis of the severity/
activity of clinical symptoms; in asymptomatic patients careful monitoring is often sufficient; in patients with moderate–severe manifestations, mainly
hepatitis, an attempt to eradicate the HCV infection should be carried out; severe, rapidly progressive complications should be treated with more
aggressive treatments, as in other severe systemic vasculitides. Right: sequential treatment can be attempted in those individuals with serious clinical
manifestations and in the absence of important contraindications. arthr., arthralgias; CFX, cyclophosphamide; CH, chronic hepatitis; CS, corticosteroid; LAC-diet, low-antigen-content diet; MPGN, membranoproliferative glomerulonephritis; peg-IFN, pegylated interferon; Purp., purpura; RIBA,
ribavirin; weak., weakness.
60 Vasculitis syndromes
endocrine disorders, and in rare cases, systemic autoimmune diseases [5,11,79,85–88]. The immunomodulating effect of a-interferon may explain its clinical
efficacy in HCV-negative cryoglobulinemic vasculitis
patients [89].
In the near future, a vaccine-based therapy with recombinant HCV proteins [90] may prevent the appearance
of extra-hepatic complications or to interrupt the selfperpetuating autoimmune mechanism of cryoglobulinemic vasculitis.
Pathogenetic/symptomatic treatments
A short time course of cyclophosphamide (1–2 mg/kg
body weight daily, for 2–3 months) in association with
high dosage of steroids or plasma exchange may be able to
treat the most severe, life-threatening complications of
cryoglobulinemic vasculitis; namely, glomerulonephritis,
recent onset sensory-motor neuropathy, or widespread
vasculitis [11,79]. Treatment with cytotoxic drugs does
not seem to affect the progression of HCV infection and,
in particular, liver involvement.
More recently, the use of rituximab, monoclonal antiCD20 antibody, has been successfully employed in cryoglobulinemic vasculitis patients, without significant side
effects [91,92,93,94]. Controlled clinical trials are
necessary in order to verify the long-term efficacy and
safety of rituximab. The impact of rituximab on HCV
viremia, which increases the baseline levels twofold [92],
suggests the possible use of combined/sequential therapy
with monoclonal anti-CD20 antibody and antiviral
agents, particularly in patients with persistent cryoglobulinemic vasculitis syndrome despite successful eradication of HCV with antiviral therapy [95,96] (C. Ferri,
personal communication). In patients with particularly
severe or resistant cryoglobulinemic vasculitis complications, some anecdotal reports suggest the possible use of
other immunomodulating or biologic therapies [97–100].
Traditionally, short time courses and low dosage of
corticosteroids and plasma exchange are classified as
‘symptomatic’ therapies; however, they may also work
as immuno-modulating or immunosuppressive treatments. Corticosteroids, alone or in association with
plasma exchange or immunosuppressors [11], may
represent the first-line intervention in the few cases of
‘essential’ cryoglobulinemic vasculitis. Low-antigencontent diet can improve the serum clearance of
immune complexes by restoring the activity of the
reticulo-endothelial system overloaded by large
amounts of circulating cryoglobulins [5,11]. Patients
with mild polyarthritis are often responsive to low
doses of steroids with or without hydroxychloroquine;
more severe cases might be successfully treated with antitumor necrosis factor a or cyclosporine A.
On the whole, the treatment of cryoglobulinemic vasculitis should be tailored for the single patient, according to
the severity of clinical symptoms (Fig. 6) [5, 11,79].
Conclusion
Cryoglobulinemic vasculitis is a multifaceted disease,
clinically characterized by both autoimmune and lymphoproliferative manifestations. Since HCV infection is the
major triggering factor of the disease, cryoglobulinemic
vasculitis represents an important model for etiopathogenetic studies of virus-driven immunological and neoplastic
disorders. Moreover, the geographical heterogeneous
distribution of HCVassociated cryoglobulinemic vasculitis
suggests an important role of other unknown infectious/
environtnental co-factors.
A clinical overlap between cryoglobulinemic vasculitis
and other diseases is quite frequent; in particular,
Sjögren’s syndrome, autoimmune hepatitis, B-cell lymphoma, other systemic vasculitides. Thereafter, some
clinico-serological and histopathological findings should
be taken into account for a correct classification/diagnosis
of cryoglobulinemic vasculitis, mainly orthostatic
purpura, serum mixed cryoglobulins, low C4, leukocytoclastic vasculitis.
The therapeutic approach to cryoglobulinemic vasculitis
is particularly difficult. An attempt to eradicate HCV
infection, when present, might represent the gold standard; however, many patients are resistant to antiviral
treatment or they may develop important side effects.
Low-dosage of steroids may be sufficient to improve the
quality of life in the majority of patients, characterized by
mild disease activity. In the presence of severe, lifethreatening complications a combined treatment with
immunesuppressors, steroids, and plasmapheresis can
be necessary.
Acknowledgements
We thank all the following people who actively contributed to our
studies mentioned in the present work: C. Mussini MD, M. Sebastiani
MD, D. Giuggioli MD, Rheumatology Unit, University of Modena e
Reggio Emilia, Italy; L. La Civita MD, G. Longombardo BS, P. Fadda
MD, Rheumatology Unit, University of Pisa; Italy; AL Zignego MD,
Department of Internal Medicine, University of Florence, Italy; S.A. Pileri
MD, Pathologic Anatomy and Haematopathology Unit, University of
Bologna, Italy.
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