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Prognostic factors in patients with hepatitis C virus infection and systemic vasculitis.

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ARTHRITIS & RHEUMATISM
Vol. 63, No. 6, June 2011, pp 1748–1757
DOI 10.1002/art.30319
© 2011, American College of Rheumatology
Prognostic Factors in Patients With Hepatitis C Virus Infection
and Systemic Vasculitis
Benjamin Terrier,1 Oren Semoun,2 David Saadoun,1 Damien Sène,1 Matthieu Resche-Rigon,2
and Patrice Cacoub1
associated with outcome. In multivariate analysis, severe fibrosis (HR 10.8) and the FFS (HR 2.49) were
significantly associated with a poor prognosis. Treatment with the combination of PEGylated interferon plus
ribavirin was associated with a good prognosis (HR
0.34), whereas treatment with immunosuppressive
agents was associated with a poor outcome, after adjustment for the severity of vasculitis (HR 4.05). Among
patients without severe fibrosis, the FFS was a good
predictor of outcome, while among those with severe
fibrosis, the severity of vasculitis had no prognostic
value.
Conclusion. At the time of the diagnosis of HCVrelated systemic vasculitis, severe liver fibrosis and the
severity of vasculitis were the main prognostic factors.
Use of antiviral agents was associated with a good
prognosis, whereas treatment with immunosuppressant
agents had a negative impact.
Objective. Hepatitis C virus (HCV)–related systemic vasculitis can cause significant morbidity and
mortality. Most studies of the prognosis of patients with
HCV-related systemic vasculitis are based on heterogeneous studies performed before the era of antiviral
therapy. The aim of this study was to analyze the
clinical, biologic, and therapeutic factors associated
with prognosis in a homogeneous series of patients with
HCV-related systemic vasculitis who were followed up
during the era of antiviral therapy.
Methods. One hundred fifty-one consecutive HCV
RNA–positive patients with vasculitis were prospectively
followed up between 1993 and 2009 and were analyzed
for clinical, biologic, and therapeutic factors associated
with survival.
Results. After a median followup period of 54
months, 32 patients (21%) had died, mainly of infection
and end-stage liver disease. The 1-year, 3-year, 5-year,
and 10-year survival rates were 96%, 86%, 75%, and
63%, respectively. Baseline factors associated with a
poor prognosis were the presence of severe liver fibrosis
(hazard ratio [HR] 5.31), central nervous system involvement (HR 2.74), kidney involvement (HR 1.91),
and heart involvement (HR 4.2). The Five-Factors Score
(FFS), a vasculitis scoring system, was significantly
Mixed cryoglobulinemia (MC) is a systemic vasculitis (1–3) caused by monoclonal B cells producing
pathogenic IgM with rheumatoid factor (RF) activity
(4). The disease expression is variable, ranging from
mild clinical symptoms (purpura, arthralgia) to lifethreatening complications (glomerulonephritis, widespread vasculitis) (1–3).
Shortly after the discovery of hepatitis C virus
(HCV) in 1989, evidence emerged that ⬎80% of cases of
MC were associated with HCV infection (5–7). In
addition, among patients with HCV-associated MC
(HCV-MC), 5–10% will experience the development of
symptomatic MC vasculitis (8,9). Less frequently, systemic vasculitis during HCV infection may occur in the
absence of detectable cryoglobulin, although the presentation and therapeutic management of such vasculitis
should be similar to that of HCV-MC vasculitis (10).
Cryoglobulinemic vasculitis can cause significant
morbidity and mortality. According to the literature, the
worst prognostic factors are age ⬎60 years and renal
1
Benjamin Terrier, MD, David Saadoun, MD, PhD, Damien
Sène, MD, PhD, Patrice Cacoub, MD, PhD: CNRS, UMR 7211,
Groupe Hospitalier Pitié-Salpétrière, Assistance Publique Hôpitaux
de Paris, and Université Pierre et Marie Curie Paris 6, Paris, France;
2
Oren Semoun, MD, Matthieu Resche-Rigon, MD, PhD: INSERM,
U717, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris,
and Université Diderot Paris 7, Paris, France.
Dr. Cacoub has received consulting fees, speaking fees,
and/or honoraria from Bristol-Myers Squibb, Pfizer, and SanofiAventis (less than $10,000 each) and from Roche, Servier, Vifer
Pharma, and Schering-Plough (more than $10,000 each).
Address correspondence to Patrice Cacoub, MD, PhD, Department of Internal Medicine, Groupe Hospitalier Pitié-Salpétrière,
47 Boulevard de l’Hôpital, 75013 Paris, France. E-mail:
patrice.cacoub@psl.aphp.fr.
Submitted for publication July 12, 2010; accepted in revised
form February 17, 2011.
1748
PROGNOSTIC FACTORS IN HCV-RELATED VASCULITIS
involvement (11,12), with renal involvement being the
main cause of death (1,11,13,14), followed by liver
involvement, cardiovascular disease, infection, and lymphoma (11). Life-threatening complications of MC vasculitis were observed less frequently (in up to 14% of
patients) and were associated with 66% mortality (15).
However, most of these findings were derived
from heterogeneous studies performed prior to the era
of antiviral therapy, which included mostly HCVpositive and HCV-negative patients with MC, who may
differ in terms of therapeutic management (i.e., use of
antiviral therapy) and outcome, in particular regarding
liver complications. Recently, we reported that the most
common causes of death in HCV-MC vasculitis were
infection, end-stage liver disease, cardiovascular disease,
and (in only a small proportion of patients) vasculitisrelated organ involvement (16), reflecting recent
changes in the therapeutic management of such patients.
In the present study, we analyzed the clinical,
biologic, and therapeutic factors associated with prognosis in a homogeneous series of 151 consecutive patients with HCV-MC vasculitis who were followed up in
a tertiary care reference center during the era of antiviral therapy.
PATIENTS AND METHODS
Patients. The study group comprised 151 consecutive
patients with HCV-related systemic vasculitis (69 men and 82
women; mean ⫾ SD age 60 ⫾ 13 years [range 31–85 years])
who were participants in a prospective and observational
cohort study and were referred between January 1, 1993 and
July 1, 2009 to the Department of Internal Medicine, Groupe
Hospitalier Pitié-Salpétrière. All patients were followed up by
the same physician (PC).
Inclusion criteria for the study were as follows: 1)
chronic active HCV infection, 2) HCV-related vasculitis, and
3) a minimum of 6 months of followup after the diagnosis.
Exclusion criteria were the presence of hepatitis B virus
surface antigen or anti–human immunodeficiency virus antibodies. Patients were considered to have HCV-related vasculitis if they had, in association with clinical manifestations of
vasculitis (purpura or cutaneous ulcers, arthralgia, myalgia,
peripheral neuropathy, renal involvement, cerebral vasculitis,
gastrointestinal involvement, cardiac involvement), the following: histologically proven vasculitis (n ⫽ 96) and/or detectable
MC with at least purpura as a clinical manifestation (n ⫽ 55).
Patients without histologically proven vasculitis but with purpura and detectable cryoglobulin were considered to have
small-vessel vasculitis, based on previously defined clinical and
biologic criteria (1,17).
For each patient, the type of vasculitis was classified
according to the Chapel Hill criteria (17). According to these
criteria and those of the American College of Rheumatology
(18), patients were classified as having MC-type small-vessel
vasculitis (n ⫽ 130) or polyarteritis nodosa (PAN)–like
medium-vessel vasculitis (n ⫽ 21). Both MC vasculitis and
1749
Table 1. Baseline characteristics of the 151 patients with HCVrelated systemic vasculitis*
Demographic features
No. of men/no. of women
Age, mean ⫾ SD years
HCV infection related
Genotype
1
2
3
4
5
Not available
HCV RNA level, mean ⫾ SD log10 IU
ALT, mean ⫾ SD ⫻ upper limit of normal
Liver Metavir score
Activity score, mean ⫾ SD
Activity score ⱖ3
Fibrosis score, mean ⫾ SD
Fibrosis score ⱖ3
Mixed cryoglobulinemia related
Cryoglobulin positive
Cryoglobulin level, mean ⫾ SD gm/liter
Type II
Type III
C4, mean ⫾ SD gm/liter
Rheumatoid factor positive
Vasculitis-related features
Deterioration of general health status
Peripheral neuropathy
Purpura
Arthralgia/arthritis
Kidney involvement
Myalgia
Central nervous system involvement
Gastrointestinal tract involvement
Heart involvement
B cell non-Hodgkin’s lymphoma
69/82
60 ⫾ 13
84/136 (62)
22/136 (16)
13/136 (10)
11/136 (8)
6/136 (4)
15
5.9 ⫾ 0.9
1.9 ⫾ 1.2
1.3 ⫾ 0.8
10/136 (7)
2.0 ⫾ 1.2
48/146 (33)
135/151 (89)
1.32 ⫾ 1.62
110 (82)
25 (18)
0.09 ⫾ 0.09
97/129 (75)
35/151 (23)
111/151 (74)
104/151 (69)
76/151 (50)
50/151 (33)
23/151 (15)
14/151 (9)
12/151 (8)
6/151 (4)
22/151 (14)
* Except where indicated otherwise, values are the number of patients/
number of patients assessed (%). HCV ⫽ hepatitis C virus; ALT ⫽
alanine aminotransferase.
PAN-type vasculitis were included in the same analysis of the
whole cohort to assess the prognostic factors for survival,
because of the low number of patients and events (deaths) in
the PAN-type vasculitis group, and because a previous study
demonstrated that the type of vasculitis did not have an impact
on survival (19).
For each patient, clinical and biologic data were recorded at the time of the initial evaluation, during followup,
and at the end of followup. Clinical data included the following: age, sex, deterioration of general health status (asthenia
and/or weight loss ⱖ10% of initial body weight), arthralgia,
myalgia, and cutaneous, neurologic, gastrointestinal, and cardiac involvement. Severe gastrointestinal involvement was
defined as intestinal bleeding and/or an acute abdomen requiring surgery. Laboratory evaluation included a complete blood
cell count, serum chemistry profile, rheumatoid factor analysis,
and determination of the level of the serum C4 fraction of
complement and the cryoglobulin level. A urinalysis was also
completed to screen for hematuria, and a 24-hour urine
collection was performed to quantify daily excretion of protein.
Cryoglobulin levels were measured and classified as
previously described (20). The presence of MC was defined by
1750
TERRIER ET AL
Table 2. Baseline epidemiologic, virologic, clinical, and biologic factors associated with outcome in the
151 patients with HCV-related systemic vasculitis*
Variable
Demographic features
Age, years
ⱕ65
⬎65
Sex
Female
Male
HCV infection-related features
Metavir activity score
0–2
3–4
Metavir fibrosis score
0–2
3–4
Genotype
1
2
3
4
5
Vasculitis-related features
Deterioration of general health
Absent
Present
Arthralgia/arthritis
Absent
Present
Myalgias
Absent
Present
Purpura
Absent
Present
Peripheral neuropathy
Absent
Present
Type of peripheral neuropathy
Multiple mononeuropathy
Polyneuropathy
CNS involvement
Absent
Present
Kidney involvement
Absent
Present
GI involvement
Absent
Present
Severe GI involvement
Absent
Present
Heart involvement
Absent
Present
B cell NHL
Absent
Present
Type of vasculitis
Mixed cryoglobulinemia
Polyarteritis nodosa
Biologic features
Creatininemia ⬎140 ␮moles/liter
Absent
Present
No. (% of death)†
HR (95% CI)‡
P
96 (10.42)
55 (40)
1
4.55 (2.51–11.06)
⬍0.0001
82 (17.07)
69 (26.09)
1
1.5 (0.75–3.02)
126 (23.81)
10 (20)
1
1.4 (0.33–5.96)
98 (11.22)
48 (43.75)
1
5.31 (2.53–11.14)
84 (22.62)
22 (18.18)
13 (15.38)
11 (9.09)
6 (16.67)
1
0.65 (0.22–1.9)
0.78 (0.18–3.35)
0.4 (0.05–3)
0.7 (0.09–5.23)
116 (18.97)
35 (28.57)
1
1.79 (0.84–3.78)
75 (21.33)
76 (21.05)
1
0.62 (0.31–1.25)
128 (21.09)
23 (21.74)
1
0.93 (0.36–2.42)
47 (25.53)
104 (19.23)
1
0.61 (0.3–1.26)
40 (15)
111 (23.42)
1
1.52 (0.63–3.7)
28 (21.43)
82 (24.39)
1
1.42 (0.57–3.56)
137 (18.98)
14 (42.86)
1
2.74 (1.12–6.7)
101 (18.81)
50 (26)
1
1.91 (0.94–3.87)
139 (21.58)
12 (16.66)
1
0.58 (0.14–2.45)
144 (21.53)
7 (14.28)
1
0.45 (0.06–3.28)
0.25
0.64
⬍0.0001
0.84
0.13
0.18
0.88
0.18
0.35
0.6
0.027
0.07
0.46
0.43
0.038
145 (20.69)
6 (33.33)
1
4.2 (0.96–18.35)
0.59
129 (20.16)
22 (27.27)
1
1.27 (0.52–3.1)
121 (21.49)
30 (20)
1
0.85 (0.35–2.07)
120 (17.5)
31 (35.48)
1
2.56 (1.23–5.32)
0.72
0.009
PROGNOSTIC FACTORS IN HCV-RELATED VASCULITIS
Table 2.
1751
Cont’d
Variable
Hematuria
Absent
Present
Proteinuria ⬎1 gm/day
Absent
Present
Type II MC
Absent
Present
Cryoglobulin level ⬎1 gm/liter
Absent
Present
Low C4 level
Absent
Present
Rheumatoid factor positivity
Absent
Present
No. (% of death)†
HR (95% CI)‡
P
0.036
115 (19.13)
36 (27.78)
1
2.19 (1.03–4.66)
113 (17.7)
38 (31.58)
1
2.34 (1.14–4.81)
37 (29.73)
110 (18.18)
1
0.63 (0.3–1.32)
80 (26.25)
47 (14.89)
1
0.56 (0.24–1.33)
26 (23.08)
93 (18.28)
1
0.79 (0.29–2.09)
32 (37.5)
97 (16.49)
1
0.49 (0.23–1.03)
0.017
0.22
0.19
0.61
0.055
* Data for some patients were missing. HCV ⫽ hepatitis C virus; HR ⫽ hazard ratio; 95% CI ⫽ 95%
confidence interval; CNS ⫽ central nervous system; GI ⫽ gastrointestinal; NHL ⫽ non-Hodgkin’s
lymphoma.
† Values are the number of patients according to the presence or absence of each variable (proportion of
patients who died, according to the presence or absence of each variable).
‡ By univariate analysis.
a serum cryoglobulin level ⬎0.05 gm/liter on at least 2 occasions. Virologic and immunologic serum markers, HCV antibodies, and RNA were detected as previously described (21).
HCV genotyping was performed using a second-generation
line probe assay (LiPA; Innogenetics). Liver damage was
evaluated according to the previously validated Metavir scoring system (22), either to interpret a liver biopsy (n ⫽ 124) or
using noninvasive biochemical markers (n ⫽ 27) (23). Both
histologic scoring and noninvasive scoring of liver fibrosis were
included in the same analysis to assess the prognostic impact of
severe fibrosis on survival. The diagnosis of B cell nonHodgkin’s lymphoma (NHL) was based on World Health
Organization criteria (24).
The Five-Factors Score (FFS), a prognosis scoring
system described by Guillevin et al (25) and used for the
management of patients with PAN and Churg-Strauss syndrome, was retrospectively evaluated in the present cohort of
patients with HCV-related systemic vasculitis. However, the
FFS has never been previously assessed for patients with
HCV-related vasculitis and was not intended for use in MC
vasculitis. The FFS is based on the following 5 clinical items
(the presence of each is accorded 1 point, for a maximum
possible score of 5): proteinuria ⬎1 gm/day, renal insufficiency
(serum creatinine level ⬎140 ␮moles/liter), cardiomyopathy,
severe gastrointestinal involvement, and central nervous system involvement. The FFS was calculated only at the time of
the diagnosis of vasculitis, and the baseline clinical and biologic
features required for the FFS were available for all patients.
The time of therapeutic management and treatment-related
data were also recorded.
Response to antiviral therapy. The clinical response of
vasculitis to antiviral treatment was defined by analyzing the
course of the following main clinical signs: skin involvement
(absence of purpura), peripheral neuropathy (clinical and/or
electrophysiologic improvement at 2 successive examinations),
renal involvement (normalization of serum creatinine level and
disappearance of proteinuria), and absence of arthralgia. A
complete clinical response was defined as an improvement in
all baseline clinical manifestations. A partial response was
defined as improvement in at least half of the baseline clinical
manifestations. All patients who were not classified as having a
partial or complete response were classified as nonresponders.
A complete immunologic response was defined as the absence
of serum cryoglobulin, and a partial immunologic response was
defined as a ⬎50% decrease in the baseline cryoglobulin level.
Relapse was defined as the reappearance of clinical signs of
vasculitis. A sustained virologic response was defined as the
absence of detectable serum HCV RNA (⬍12 IU/ml) 6
months after discontinuation of antiviral treatment; the remaining patients were classified as virologic nonresponders.
Assessment of the standardized mortality ratio
(SMR). To compare the observed mortality with the expected
mortality, an SMR was used. The SMR is the ratio of the
observed patient mortality and the mortality in the total
French population of individuals with the corresponding sex
and year of birth. Expected mortality rates were obtained from
the latest data from the French national Statistical Institute
(INSEE; http://www.ined.fr/fr/pop_chiffres/france/mortalite_
causes_deces/deces_sexe_age), and only observations made
before 2007 were considered.
Statistical analysis. For the current study, the data for
categorical variables are summarized as frequencies and percentages, and quantitative variables are presented as the
mean ⫾ SD or medians, 25th and 75th percentiles, and
minimum and maximum, as appropriate. Survival curves and
their 95% confidence intervals (95% CIs) were estimated using
the Kaplan-Meier method. The association of the variables
with the occurrence of death was assessed using a univariate
1752
TERRIER ET AL
Figure 1. Kaplan-Meier estimates of the survival rates for the 151 patients with
hepatitis C virus–related systemic vasculitis. Dashed lines show the 95% confidence
interval (95% CI).
Cox proportional hazards model. The proportional hazards
assumption for the Cox regression model fit were tested for all
of the variables. The log-linearity of the quantitative variables
was tested using generalized additive models. Age was split
into 2 categories according to the estimated median. Multivariate Cox proportional hazards models were performed afterward and adjusted on the dichotomized Metavir fibrosis score
(cutoff ⱖ3) that had the highest hazard ratio (HR). The
followup length (median, 25th and 75th percentiles) was
calculated using an inverse Kaplan-Meier method. A multivariate Cox proportional hazards model was performed, including
the dichotomized Metavir F score (cutoff ⱖ3), the FFS, and
their interaction. Patients lost to followup were censored on
the date of their last clinical evaluation. All tests were 2-sided
at the 0.05 significance level. Analyses were performed using
the R.2.10.1 statistical package (online at http://www.Rproject.org).
RESULTS
Characteristics of the patients. One hundred
fifty-one patients with HCV-related vasculitis were included. The characteristics of the patients are shown in
Table 1. The main HCV genotype was type 1 (62%), and
48 of 146 patients (33%) had severe liver fibrosis, as
defined by a Metavir score of ⱖ3 (including grade F3 in
23 patients and grade F4 in 25 patients). The main
clinical features of HCV-related vasculitis included pe-
ripheral neuropathy (74%), purpura (69%), arthralgia/
arthritis (50%), kidney involvement (33%), central nervous system involvement (9%), gastrointestinal involvement (8%), and heart involvement (4%). Twenty-two
patients (14%) had B cell NHL. MC was diagnosed in
121 patients, while 30 patients had PAN-type vasculitis
(Table 2). All but 16 patients had detectable cryoglobulin, with a mean ⫾ SD level of 1.32 ⫾ 1.62 gm/liter
(range 0.05–7). The mean ⫾ SD serum C4 level was
0.09 ⫾ 0.09 gm/liter (range 0.01–0.41).
Outcome. After a median followup of 54 months
(interquartile range 26–89 months), 32 patients (21%)
had died, including 26 patients with MC vasculitis and
6 with PAN-type vasculitis. Causes of death included
infection (n ⫽ 10), end-stage liver disease (n ⫽ 10
[including hepatocellular carcinoma in 4 patients]), nonliver malignancy (n ⫽ 4 [including lung cancer in 2
patients, B cell NHL in 1 patient, and T cell lymphoma
in 1 patient), cardiovascular disease (n ⫽ 4), renal
failure (n ⫽ 2), central nervous system vasculitis (n ⫽ 2),
and unknown cause (n ⫽ 2). Two patients died of both
infection and end-stage liver disease. The 1-year, 3-year,
5-year, and 10-year survival rates were 96% (95% CI
93–99), 86% (95% CI 80–92), 75% (95% CI 67–84), and
63% (95% CI 52–76), respectively (Figure 1). Mortality
PROGNOSTIC FACTORS IN HCV-RELATED VASCULITIS
1753
Figure 2. Kaplan-Meier estimates of the survival rates for the 151 patients with hepatitis C virus–related systemic vasculitis according to the
presence or absence at baseline of severe liver fibrosis (A), heart involvement (B), central nervous system (CNS) involvement (C), and proteinuria
(D), the serum creatinine level (E), and the Five-Factors Score (FFS) (F). Survival rates were compared using the log rank test in univariate analysis.
Metavir fibrosis scores (F) of 3–4 indicate severe liver fibrosis; scores of 0–2 indicate the absence of liver fibrosis.
Figure 3. Kaplan-Meier estimates of the survival rates for the 151 patients with hepatitis C
virus–related systemic vasculitis, according to the Metavir fibrosis score (F) and the Five-Factors
Score (FFS). Values in brackets are the 95% confidence intervals. NA ⫽ not applicable.
1754
TERRIER ET AL
Table 3. Treatments and response to therapy–related factors associated with outcome in the 151
patients with HCV-related systemic vasculitis*
Variable
Antiviral therapy
PEG-IFN␣ plus ribavirin
Not used
Used
IFN plus ribavirin
Not used
Used
IFN monotherapy
Not used
Used
Cotreatment
Corticosteroids
Not used
Used
Plasmapheresis
Not used
Used
Immunosuppressive agents
Not used
Used
Rituximab
Not used
Used
Response to therapy
Clinical response
None
Partial
Complete
Immunologic response
None
Partial
Complete
Virologic response
Nonsustained
Sustained
No. (% of death)†
HR (95% CI)‡
51 (41.18)
100 (11)
1
0.34 (0.16–0.67)
126 (18.25)
25 (36)
1
1.23 (0.55–2.86)
137 (17.52)
14 (57.14)
1
3.08 (1.79–18.81)
92 (14.13)
59 (32.2)
1
2.25 (1.06–4.76)
124 (17.74)
27 (37.04)
1
1.90 (0.90–5.22)
138 (17.39)
13 (61.54)
1
4.63 (2.02–10.58)
110 (25.45)
41 (9.76)
1
0.78 (0.28–2.15)
20 (65)
31 (19.35)
83 (10.84)
1
0.25 (0.09–0.66)
0.1 (0.04–0.23)
24 (54.17)
33 (9.09)
61 (11.48)
1
0.17 (0.05–0.58)
0.15 (0.06–0.38)
67 (31.34)
59 (8.47)
1
0.19 (0.07–0.52)
P
0.002
0.3
0.003
0.03
0.09
⬍0.0001
0.63
⬍0.0001
⬍0.0001
0.0004
* HCV ⫽ hepatitis C virus; HR ⫽ hazard ratio; 95% CI ⫽ 95% confidence interval; PEG-IFN␣ ⫽
PEGylated interferon ␣.
† Values are the number of patients according to the presence or absence of each variable (proportion of
patients who died, according to the presence or absence of each variable).
‡ By univariate analysis.
was increased among patients with HCV-related vasculitis compared with that among individuals in the total
French population with the corresponding sex and year
of birth (SMR 2.7 [95% CI 1.8–3.9]).
Prognostic factors at baseline. Baseline factors
associated with a poor prognosis were determined by
univariate analysis (Table 2 and Figure 2). Age ⬎65
years was associated with a poor prognosis (HR 4.55,
95% CI 2.51–11.06 [P ⬍ 0.0001]). The only HCV-related
feature associated with a poor prognosis was the presence of severe liver fibrosis as defined by a Metavir
fibrosis score of ⱖ3 (HR 5.31, 95% CI 2.53–11.14 [P ⬍
0.0001]). Clinical manifestations significantly associated
with a poor prognosis were central nervous system
involvement (HR 2.74, 95% CI 1.12–6.7 [P ⫽ 0.027]),
kidney involvement (HR 1.91, 95% CI 0.94–3.87 [P ⫽
0.07]), and heart involvement (HR 4.2, 95% CI 0.96–
18.35 [P ⫽ 0.038]). Neither gastrointestinal involvement
nor the type of vasculitis (MC versus PAN) was associated with a poor outcome. Biologic features associated
with a poor prognosis were a serum creatinine level
⬎140 ␮moles/liter (HR 2.56, 95% CI 1.23–5.32 [P ⫽
0.009]), hematuria (HR 2.19, 95% CI 1.03–4.66 [P ⫽
0.036]), and proteinuria ⬎1 gm/day (HR 2.34, 95% CI
1.14–4.81 [P ⫽ 0.017]). The FFS was significantly associated with outcome in patients with HCV-related systemic vasculitis (HR 1.85 [95% CI 0.69–6.47] and HR
2.62 [95% CI 1.30–9.22] in patients with scores of 0–1
and ⬎1, respectively; P ⫽ 0.038).
In multivariate analysis, the Metavir fibrosis
score (HR 10.8, 95% CI 3.63–32.14 [P ⬍ 0.0001]) and
the FFS (HR 2.49, 95% CI 1.29–4.8 [P ⫽ 0.007])
PROGNOSTIC FACTORS IN HCV-RELATED VASCULITIS
were significantly associated with a poor prognosis.
Management of patients after 2001, i.e., after the introduction of combination treatment with PEGylated
interferon ␣ (PEG-IFN␣) plus ribavirin in our cohort,
was associated with a good prognosis (HR 0.4, 95% CI
0.19–0.81 [P ⫽ 0.009]), whereas no significant difference
in clinical and biologic presentation, liver fibrosis, and
severity of vasculitis was noted between patients treated
before 2001 and those treated after 2001 (data not
shown).
The interactions between significant prognostic
factors were evaluated, i.e., liver fibrosis was assessed
using the Metavir fibrosis score, and the severity of
vasculitis was assessed using the FFS. Survival curves
and rates according to the severity of liver fibrosis, the
severity of vasculitis, and their interactions are shown in
Figure 3. In patients without severe liver fibrosis (Metavir score ⱕ2), the FFS was a good predictor of outcome
(HR 1, 2.49, and 6.2 in patients with scores of 0, 1, and
⬎1, respectively). In contrast, in patients with severe
liver fibrosis (Metavir score ⱖ3), the only factor associated with prognosis was the Metavir fibrosis score, while
the severity of vasculitis assessed using the FFS no
longer had prognostic value (HR 10.8, HR 10.25, and
HR 9.74 in patients with scores of 0, 1, and ⬎1,
respectively).
Prognostic factors during followup. The factors
associated with outcome during followup, i.e., the treatments used and the response to therapy, are shown in
Table 3. Treatment with PEG-IFN␣ plus ribavirin was
associated with a good prognosis (HR 0.34, 95% CI
0.16–0.67 [P ⫽ 0.002]), whereas IFN monotherapy was
associated with a poor prognosis (HR 3.08, 95% CI
1.79–18.81 [P ⫽ 0.003]). Corticosteroids (HR 2.25, 95%
CI 1.06–4.76 [P ⫽ 0.03]) and immunosuppressive agents
(HR 4.63, 95% CI 2.02–10.58 [P ⬍ 0.0001]) were both
associated with a poor outcome in univariate analysis.
Treatment with plasmapheresis (HR 1.90, 95% CI 0.90–
5.22 [P ⫽ 0.09]) and rituximab (HR 0.78, 95% CI
0.28–2.15 [P ⫽ 0.63]) were not associated with a poor
outcome. After adjustment for the severity of vasculitis,
treatment with immunosuppressive agents was still associated with a poor prognosis (HR 4.05, 95% CI 1.75–9.36
[P ⫽ 0.001]), while treatment with corticosteroids was
not (HR 1.79, 95% CI 0.77–4.16 [P ⫽ 0.17]). Regarding
response to therapy, a complete clinical response (HR
0.1, 95% CI 0.04–0.23 [P ⬍ 0.0001]), a complete immunologic response (HR 0.15, 95% CI 0.06–0.38 [P ⬍
0.0001]), and a sustained virologic response (HR 0.19,
95% CI 0.07–0.52 [P ⫽ 0.0004]) were associated with a
good prognosis.
1755
DISCUSSION
In the present study, we analyzed prognostic
factors in patients with HCV-related systemic vasculitis,
during the era of antiviral therapy. The most striking
observations were the poor long-term prognosis of patients with HCV-related systemic vasculitis, the major
prognostic impact of liver fibrosis at the time of the
diagnosis of vasculitis, the negative impact of the severity of vasculitis efficiently assessed by the FFS, and the
interaction between these 2 prognostic factors.
Patients with HCV-related systemic vasculitis
have a poor long-term prognosis, with 5-year and 10year survival rates of 75% and 63%, respectively. Their
prognosis is comparable with that of patients with hepatitis B virus–related vasculitis, for whom the 5-year and
10-year survival rates are 73% and 60%, respectively
(26). In contrast, the long-term prognosis of patients
with chronic HCV infection in the absence of vasculitis
is better, with a 5-year survival rate of 95% (27); in a
recent study in Norway, the 14-year survival rate was
found to be 88% (28). The poor prognosis of patients
with HCV-related vasculitis compared with that for
patients with chronic HCV infection without vasculitis
could be related, in addition to vasculitis-related manifestations, to a higher rate of advanced liver fibrosis in
the former group of patients. In our cohort, one-third of
patients had severe liver fibrosis at the baseline evaluation. This point is also supported by previous studies
showing that patients with HCV-related MC have a
higher rate of cirrhosis and mortality than their counterparts without MC (29,30). In addition, patients with
HCV-related vasculitis had increased mortality compared with individuals in the total French population
with the corresponding sex and year of birth. The use of
SMRs is of interest to give a measure of the marginal
death rate linked to HCV-related vasculitis. However,
SMRs do not account for potential differences in characteristics between the study and reference populations
other than the variables used for stratifying the mortality
rates.
In previous studies focusing on MC-related vasculitis, advanced liver disease was rarely shown to be
associated with outcome, and liver complications accounted for ⬃10–15% of the causes of death, far behind MC-related complications and renal involvement
(1,11–14). These discrepancies may be explained by the
heterogeneity regarding HCV positivity status and the
time of inclusion of the patients in previous studies,
when the management of vasculitis-related complications was less efficient. In addition, better combinations
of antiviral agents have emerged in the past decade,
1756
leading to a change in the management and prognosis
of HCV-infected patients. The positive impact of efficient antiviral combination treatment is supported by
the fact that patients managed after 2001 (i.e., after
the introduction of combination treatment with PEGIFN␣ plus ribavirin in our cohort) had a better prognosis than the others, whereas these patients did not
differ regarding clinical and biologic presentation, liver
fibrosis, and severity of vasculitis. In contrast, the prognosis of patients treated with previous antiviral regimens providing lower sustained virologic response rate
(i.e., standard IFN␣ monotherapy or standard treatment with IFN␣ plus ribavirin) was poorer compared
with the prognosis of those treated with PEG–IFN␣ plus
ribavirin.
Besides liver fibrosis severity, severe vasculitisrelated manifestations were significantly associated with
a poor outcome. These findings are consistent with
studies focusing on patients with primary systemic vasculitides. Interestingly, the FFS, validated in patients
with PAN and Churg-Strauss syndrome (25), was shown
to be a good predictor of outcome in patients with
HCV-related systemic vasculitis. In primary systemic
vasculitides, patients with an FFS ⱖ1 are usually treated
with the combination of corticosteroids and immunosuppressive agents, such as cyclophosphamide, in order
to improve outcome (25,31). Currently, the standard
of care for patients with HCV-related vasculitis includes an optimal antiviral therapy (PEG-IFN␣ plus
ribavirin) but no systematic use of immunosuppressive
agents (21,32). The analysis of factors associated with
outcome during followup showed that treatment
with PEG-IFN␣ plus ribavirin was significantly associated with a good prognosis, while the use of immunosuppressive therapy, most often in combination with
high-dose corticosteroids, was associated with a poor
outcome, even after adjustment for the severity of
vasculitis.
We used a multivariable model, adjusted notably
for the severity of vasculitis, to assess the prognostic
impact of treatments, which is the conventional modeling approach used to handle and reduce the impact on
such confounders in estimations (33). The use of other
approaches such as propensity score methods should be
avoided in our case because of the small number of
patients and the fact that propensity score approaches
are developed to evaluate only one rather than several
treatments. The analysis of causes of death in our cohort of patients revealed that the main causes were
HCV-related hepatopathy and severe infections in patients treated with immunosuppressive agents, whereas
vasculitis-related deaths were less frequent. These find-
TERRIER ET AL
ings provide evidence on the morbidity and mortality
related to the use of immunosuppressive agents in such
patients. In contrast, short-term treatment with corticosteroids, rituximab, and/or plasmapheresis, which is not
associated with a poor outcome, could be used according
to initial presentation in order to control severe and
life-threatening manifestations. The absence of a negative impact of rituximab and/or plasmapheresis in patients with HCV-related vasculitis may be explained
by the fact that such treatments are frequently introduced in combination with antiviral agents in order to
shorten the period of time to clinical remission and
improve renal response and cryoglobulin clearance
rates, but rarely in association with high-dose corticosteroids.
Last, using a multivariate model, we analyzed
the interaction between liver fibrosis and severity of
vasculitis as assessed by the FFS. We showed that in
patients without severe liver fibrosis, the FFS was a
good predictor of outcome. However, in patients with
severe liver fibrosis, the severity of vasculitis at baseline
was not associated with outcome, with the Metavir
fibrosis score being the only remaining prognostic factor.
These findings may help clinicians in the management of
patients with HCV-related systemic vasculitis, in particular those with advanced liver fibrosis. It is noteworthy
that in our experience, the use of IFN-based combinations and/or rituximab remains safe in HCV RNA–
positive patients with systemic vasculitis and advanced
liver fibrosis.
Limitations of the study include its open-label
and observational design. However, the baseline clinical
and biologic findings and information regarding the
efficacy and tolerance of treatments were available for
almost all patients, except for a very low proportion
(5%) who were lost to followup within the first 12
months. In addition, all patients were treated at the
same center by the same physician, using homogeneous
management. We cannot exclude the possibility that
statistically nonsignificant factors may be clinically relevant, and that the observed statistical power may be
lower than expected.
In conclusion, HCV RNA–positive patients with
systemic vasculitis have a poor long-term outcome. At
the time of the diagnosis of vasculitis, the main prognostic factors include liver fibrosis and vasculitis-related
organ involvement, but in patients with severe liver
fibrosis, the severity of vasculitis is not associated with
outcome. In contrast with treatment using immunosuppressive agents in primary systemic vasculitides, treatment with immunosuppressive agents seems to have a
PROGNOSTIC FACTORS IN HCV-RELATED VASCULITIS
negative impact on survival, regardless of the severity of
vasculitis.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Cacoub had full access to all of
the data in the study and takes responsibility for the integrity of the
data and the accuracy of the data analysis.
Study conception and design. Terrier, Cacoub.
Acquisition of data. Terrier, Saadoun, Sène, Cacoub.
Analysis and interpretation of data. Terrier, Semoun, Resche-Rigon,
Cacoub.
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