Introduction
Primary vasculitis is a systemic disease of unknown
etiology (1–3). The main pathological features are
vascular wall inflammation and fibrinoid necrosis. It is closely
related with the anti-neutrophil cytoplasmic antibody (ANCA)
(4) and is known as the primary
ANCA-associated small-vessel vasculitis (primary AAV). According to
the Chapel Hill Consensus Conference in 1994, AASV
(antibody-associated systemic vasculitis) includes granulomatosis
with polyangiitis (GPA, previously known as Wegener’s
granulomatosis), microscopic polyangiitis (MPA) and eosinophilic
granulomatosis with polyangiitis (EGPA, formerly known as
Churg-Strauss vasculitis or Churg-Strauss) (5–7).
AASV involves the systemic small vessels and multiple organs.
Research shows that the renal impairment is more frequently
observed and more severe in AASV, and approximately half of the
patients have this manifestation in the early stage of the disease.
Propylthiouracil (PTU) is a drug frequently used to treat
hyperthyroidism (8) and its side
effects are frequently reported. In recent years, PTU-induced
ANCA-associated small-vessel vasculitis, also known as
PTU-associated small-vessel vasculitis, is increasingly reported
(9,10). Renal impairment is the most
frequent and severe symptom observed. The majority of previous
reports indicate that PTU-associated small-vessel vasculitis has a
better prognosis than the ANCA-induced variant but pathological and
clinical comparisons of the two are uncommon. This study analyzes
the similarities and differences in the renal impairment of both
forms from the pathological and clinical aspects. The results
should assist in diagnosis and treatment.
Subjects and methods
Research subjects
Patients with PTU-associated small-vessel vasculitis
and patients with primary AAV diagnosed from 2002 to 2011 were
selected as the research subjects. The diagnostic criteria for
PTU-associated small-vessel vasculitis were as follows: i) The
patient had manifestations of vasculitis, which coincided with
taking PTU; ii) Positive serum ANCA; iii) Other diseases that cause
vasculitis were excluded, such as malignant tumor and infection.
The diagnostic criteria for primary AAV referred to related
diagnostic criteria provided by the Chapel Hill Consensus
Conference in 1994 and the American College of Rheumatology (ACR).
All patients had manifestations of renal impairment, such as
hematuria, proteinuria, renal insufficiency and hypertension and
their renal biopsy was suggestive of vasculitis. This study was
conducted in accordance with the declaration of Helsinki and with
the approval of the Ethics Committee of the Second Affiliated
Hospital of Fujian Medical University. Written informed consent was
obtained from all participants.
Clinical and laboratory examination
According to the analysis of the general
characteristics of the patients (age and gender) and renal
impairment (including gross hematuria, 24 h proteinuria content and
serum creatinine), perinuclear anti-neutrophil cytoplasmic antibody
(p-ANCA) and cytoplasmic anti-neutrophil cytoplasmic antibody
(c-ANCA) were detected using indirect immunofluorescence (IIF) and
myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA were
detected using enzyme-linked immunosorbent assay (ELISA).
Renal biopsy
All patients underwent percutaneous renal biopsy to
observe through routine light microscopy, immunofluorescence and
electron microscopy the number of glomerular crescents (including
cellular crescents, fibrocellular crescents and fibrous crescents),
glomerular capillary loop necrosis and renal tubulointerstitial
lesions.
Treatment
PTU-induced small-vessel vasculitis was treated
based on the following principles (11): i) immediate withdrawal of PTU; ii)
if necessary, separate use of hormones or use of hormones in
combination with cyclophosphamide depending on the state of
illness. Primary AAV was treated referring to previous reports in
the literature.
The curative effect was classified into complete,
partial and no remission as per criteria in the literature
(12).
Statistical analysis
SPSS version 14.0 was used for statistical analysis
with the statistical data expressed as mean ± SD. P<0.05 was
considered to indicate a statistically significant result.
Results
General characteristics
This study included 10 patients with PTU-induced
small-vessel vasculitis and 18 patients with primary AAV (including
16 patients with MPA, 1 patient with GPA and 1 patient with EGPA).
Compared with primary AAV, the patients with PTU-induced
small-vessel vasculitis were mostly female and young when falling
ill (P<0.05, Table I).
 | Table IComparison of the general
characteristics of both groups. |
Table I
Comparison of the general
characteristics of both groups.
| PTU-associated
small-vessel vasculitis (n=10) | Primary AAV
(n=18) | Statistical data | P-value |
|---|
| Number of female
patients | 9 (90.0%) | 7 (38.9%) | - | 0.01 |
| Age of onset | 39.2±8.4 | 60.4±10.1 | t=−5.6 | 0.00 |
Laboratory examination
Compared with primary AAV, the patients with
PTU-induced small-vessel vasculitis had higher positive rate of
p-ANCA (P<0.05, Table II), as
was indicated by the indirect immunofluorescence. ELISA showed that
1 patient with PTU-induced small-vessel vasculitis demonstrated
positive MPO-ANCA and PR3-ANCA but none of the patients with
primary AAV presented double positive, showing that the patients
with PTU-induced small-vessel vasculitis had a higher proportion of
dysimmunity. A few patients with such disease had gross hematuria
(P<0.05, Table II) and all of
the patients with such disease had lower 24 h proteinuria content,
lower serum creatinine (P<0.05, Table II) and milder renal impairment.
| Table IIComparison of the laboratory
examination of both groups. |
Table II
Comparison of the laboratory
examination of both groups.
| PTU-associated
small-vessel vasculitis (n=10) | Primary AAV
(n=18) | Statistical data | P-value |
|---|
| Indirect
immunofluorescence of ANCA | | | | |
| Number of patients
with p-ANCA | 10 (100.0%) | 10 (55.6%) | - | 0.02 |
| Number of patients
with c-ANCA | 0 (00.0%) | 8 (44.4%) | - | 0.02 |
| ELISA of ANCA | | | | |
| Number of patients
with MPO-ANCA only | 8 (80.0%) | 11 (61.1%) | | |
| Number of patients
with PR3-ANCA only | 1 (10.0%) | 7 (38.9%) |
χ2=0.63 | 0.42 |
| Number of patients
with double positive | 1 (10.0%) | 1 (10.0%) | 0 (0.0%) | |
| Number of patients
with gross hematuria | 1 (10.0%) | 10 (55.6%) | - | 0.04 |
| 24 h proteinuria
content (mg/24 h) | 578.5±119.7 | 1541.7±334.7 | t=−11.0 | 0.00 |
| Creatinine
(μmol/l) | 159.9±50.9 | 567.6±112.1 | t=−13.1 | 0.00 |
Renal biopsy
Compared with primary AAV, the patients with
PTU-induced small vasculitis had a lower proportion of crescents
(P<0.05, Table III), a lower
proportion of glomerular capillary loop necrosis (P<0.05), a
lower proportion of interstitial fibrosis (P<0.05, Table III), a lower proportion of
arteriolar fibrinoid necrosis (P<0.05) and a lower proportion of
inflammatory cell infiltration (P<0.05, Table III.). These data suggested that the
patients with PTU-induced small-vessel vasculitis had milder
histopathological lesions.
| Table IIIComparison of the renal biopsy of both
groups. |
Table III
Comparison of the renal biopsy of both
groups.
| PTU associated
small-vessel vasculitis (n=10) | Primary AAV
(n=18) | Statistical data | P-value |
|---|
| Proportion of
cellular crescents (%) | 11.9±5.8 | 45.3±9.9 | t=−9.7 | 0.00 |
| Proportion of
fibrocellular crescents (%) | 2.5±1.8 | 20.1±7.0 | t=−7.8 | 0.00 |
| Proportion of fibrous
crescents (%) | 3.9±2.2 | 16.3±3.9 | t=−9.3 | 0.00 |
| Glomerular capillary
loop necrosis | 2 (20.0%) | 12 (66.7%) | − | 0.04 |
| Interstitial
fibrosis | 1 (10.0%) | 10 (55.6%) | − | 0.04 |
| Arteriolar fibrinoid
necrosis | 1 (10.0%) | 11 (61.1%) | − | 0.04 |
| Inflammatory cell
infiltration | 1 (20.0%) | 13 (72.2%) | − | 0.00 |
Treatment and outcomes
Among the patients with PTU-induced small-vessel
vasculitis, 3 were not administered any hormone or cytotoxic drug
following the withdrawal of PTU, 6 of them were administered
hormone only and 1 of them was administered hormone in combination
with cyclophosphamide. All patients with primary AAV were
administered hormone and cytotoxic drugs, 2 were treated with blood
purification (13) and the
difference was statistically significant (Z=−4.7, P=0.00). All
patients were followed up for 9–24 months (median follow-up time of
15 months), which showed that among patients with PTU-induced
small-vessel vasculitis, 7 presented complete remission, 3
presented partial remission and none had no remission; in patients
with primary AAV, 5 patients presented complete remission, 9
patients presented partial remission and 5 patients had no
remission. The comparison showed that the difference between the
two groups was statistically significant (Z=−2.3, P=0.02).
Discussion
In 1992, Stankus and Johnson reported the first case
of PTU-induced small-vessel vasculitis (14). Since then several cases of
PTU-induced small-vessel vasculitis have been reported (15). PTU induces the generation of ANCA.
According to this report, 20–64% of patients administered PTU
progressed to positive ANCA and ∼4–6.5% of patients may progress to
vasculitis (16). It has different
pathogeneses and different clinical and pathological
characteristics from primary AAV. This paper systematically
compared the clinical and pathological characteristics of renal
impairment of both conditions. The results show that patients with
PTU-induced small-vessel vasculitis are mostly young and female
with a higher positive rate of p-ANCA, milder clinical and
pathological characteristics, easier treatment and better
prognosis.
Both the present study and a previous study
(16) show that patients with
PTU-induced small-vessel vasculitis are mostly young and female,
and patients with primary AAV are mostly old-aged without gender
difference. The cause may be that the patients with hyperthyroidism
are mainly young and female and are mainly treated using oral
drugs, 131I or surgery. 131I and surgery may
involve drawbacks such as large trauma and more complications. As a
result, these patients are mainly treated with oral drugs.
ANCA is the first autoantibody proven to be
associated with vasculitis. The target antigens of ANCA include
various ingredients in the neutrophil cytoplasm, mainly PR3 and MPO
(17,18). In the two groups of patients,
p-ANCA is more frequently observed than c-ANCA. Primary AAV is not
a disease but a group of diseases. c-ANCA and its target antigen
PR3-ANCA are more frequently observed in patients with GPA, while
p-ANCA and its target antigen MPO-ANCA are more frequently observed
in patients with MPA and EGPA (3).
In the present study, the total number of patients with MPA and
patients with EGPA was 41 while the number of GPA patients was 7.
This may explain why p-ANCA and its target antigen MPO-ANCA are
more frequently observed in patients with primary AAV. p-ANCA is
more frequently observed in patients with PTU-induced small-vessel
vasculitis and p-ANCA and its target antigen MPO-ANCA may be
induced by PTU (19). The specific
mechanism needs to be elucidated. In this study, positive PR3-ANCA
and MPO-ANCA were only seen in patients with PTU-induced
small-vessel vasculitis and were not seen in patients with primary
AAV. The mechanism may be associated with the polyclonal activation
of B-lymphocytes. In addition to the target antigens PR3-ANCA and
MPO-ANCA, other ANCA antigens may also be detected in patients
taking PTU. This phenomenon was not found in patients with primary
AAV and the degree of renal impairment was not related to the
amount of ANCA target antigen (19–21).
The specific mechanism needs further investigation.
In the present study, compared with primary AAV,
patients with PTU-induced small-vessel vasculitis have milder renal
impairment and better prognosis. This may be associated with prompt
removal of contributing factors of the disease, as well as the low
age of patients in this group. Some studies show that old age is a
predictor for prognosis of primary AAV (22). In conclusion, patients with
PTU-induced small-vessel vasculitis have milder renal impairment
than those with primary AAV, and this may also be associated with
better prognosis.
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