Long-term outcomes of patients with propylthiouracil-induced
anti-neutrophil cytoplasmic auto-antibody-associated vasculitis
Y. Gao1,2, M. Chen1, H. Ye2, F. Yu1, X.-h. Guo2and M.-h. Zhao1
Objective. It was well known that propylthiouracil (PTU) could induce ANCA-associated vasculitis (AAV) and clinical evident vasculitis could
resolve after cessation of PTU with or without immunosuppressive therapy. However, the treatment strategy for patients with PTU-induced
AAV remained inconclusive and their long-term outcomes were lacking. The aim of our study was to summarize these data.
Methods.Fifteen patients with PTU-induced AAV, receiving immunosuppressive agents for <12 months and following over 24 months,
were selected in the current study. The clinical and pathological data, including treatment protocols and outcomes, were retrospectively
Results. All the patients were followed for a mean of 55.0 (25–98) months. PTU was discontinued upon diagnosis of PTU-induced AAV.
Immunosuppressive therapy was administrated only for patients with vital organ involvements, such as lung and kidney, and lasted only
7.9?3.3 (0.27–12) months. No relapse of vasculitis occurred during follow-up, even after withdrawal of immunosuppressive therapy. Twelve
(80%) patients remained in complete remission and one patient remained in partial remission at the latest follow-up. Two patients were
treatment resistant due to late referral and late withdrawal of PTU, both of them progressed to end-stage renal disease. For uncontrolled
hyperthyroidism on presentation, six patients switched to methimazole and none of them experienced relapse of vasculitis.
Conclusions. The long-term outcomes of patients with PTU-induced AAV were relatively good. PTU should be discontinued immediately
after diagnosis. Immunosuppressive therapy may be only used in patients with vital organ involvements, and a long-term maintenance
therapy may not be necessary.
KEY WORDS: Propylthiouracil, Vasculitis, Antineutrophil cytoplasmic antibodies, Hyperthyroidism, Therapy, Prognosis.
ANCA-associated vasculitis (AAV) is associated with high
morbidity and mortality, as well as potentially life-threatening
toxicity from immunosuppressive therapy. Thus, identification of
potentially reversible causes of AAV, such as specific drugs, is
very important . Propylthiouracil (PTU) is a common anti-
thyroid drug, which has been known to induce AAV [2–6] with
multiple ANCA antigen specificities .
Although immunosuppressive therapy remained mainstay in
patients with primary AAV, it has been reported that clinical
evident vasculitis of PTU-induced AAV could resolve merely after
cessation of PTU without immunosuppressive therapy, even in
patients with severe organ involvement such as alveolar haemor-
rhage . However, it was reported that PTU-induced AAV might
be fatal in spite of intensive immunosuppressive therapy in some
cases . Therefore, treatment strategy for patients with PTU-
induced AAV remains inconclusive. Furthermore, it has been well
known that patients with primary AAV should receive main-
tenance therapy for years after achieving remission to control
frequent relapses of vasculitis. Whether the maintenance therapy
should be administrated in the same way in patients with PTU-
induced AAV has not been determined yet. Most patients with
PTU-induced AAV might take unnecessary risks in the long-term
Regarding to the different pathogenesis between PTU-induced
AAV and primary vasculitis, we recommended different ther-
apeutic protocols for patients with PTU-induced AAV. PTU
should be discontinued immediately after diagnosis of PTU-
induced AAV; immunosuppressive therapy should be admin-
istrated only for patients with vital organ involvement, such as
lung and kidney vasculitis. Furthermore, the immunosuppressive
therapy only lasted for 6–12 months, according to disease severity,
without further maintenance therapy. In the current study, we
summarized the treatment protocols and long-term outcomes of
15 patients with PTU-induced AAV treated with the above
Materials and methods
Fifteen patients with PTU-induced AAV, diagnosed in Peking
University First Hospital during December 1999 to December
2005, were selected in the current study. They were followed up for
at least 24 months. All these patients fulfilled the 1994 Chapel Hill
Consensus Conference definition for AAV. PTU-induced AAV
was defined as following: (i) the signs and symptoms of vasculitis
were temporally related to using PTU, and regressed with its
discontinuation; (ii) serum ANCA was positive, especially those
with multi-antigenicity; (iii) medical conditions that mimicked
vasculitis were excluded, especially infections and malignancies,
and other definable types of vasculitis .
Patients with hyperthyroidism were diagnosed on the basis of
typical clinical manifestations, elevated serum-free triiodothyro-
nine (FT3) and free thyroxine (FT4) and very low or undetectable
thyrotropin. The diagnosis of Graves’ disease was based on the
fulfilment of at least one of the following classical criteria:
ophthalmopathy; a diffuse goitre; pre-tibial myxoedema and the
presence of thyrotropin receptor antibody.
This study was complied with the Helsinki declaration and was
approved by the Ethics Committee of Peking University First
Hospital. All patients gave written informed consent. Data on
clinical manifestation and laboratory results were collected upon
diagnosis and during follow-up. All the patients were revisited
every 1–3 months in the first 6 months after diagnosis of PTU-
induced AAV, and every 3–6 months during subsequent follow-up.
Sequential serum samples were collected upon diagnosis before
immunosuppressive treatment, and about every 3 months in the
first 6 months, every 6–12 months during subsequent follow-up.
1 of 6
1Department of Nephrology and2Department of Endocrinology, Peking University
First Hospital, Beijing, P.R. China.
Submitted 22 May 2008; revised version accepted 8 July 2008.
Correspondence to: M.-h. Zhao, Department of Nephrology, Peking University
First Hospital, Beijing 100034, P.R. China. E-mail: email@example.com
Rheumatology 2008; 1 of 6doi:10.1093/rheumatology/ken321
? The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org
Rheumatology Advance Access published August 1, 2008
by guest on June 2, 2013
ANCA were detected by both indirect IF (IIF) assay and antigen-
specific ELISAs as described [11, 12].
IIF assay. All sera were screened for ANCA by IIF technique
according to the manufacturer (Euroimmun, Lu ¨ beck, Germany).
The fluorescence patterns were classified as cytoplasmic ANCA
(C-ANCA) and perinuclear ANCA (P-ANCA). Slides were read
by two independent observers who were not aware of the clinical
ANCA antigens, including MPO, proteinase 3, human leucocyte
elastase (HLE), lactoferrin, cathepsin G, azurocidin and bacter-
icidal/permeability-increasing protein (BPI) [13–16], were initially
used as solid-phase ligands to detect ANCA specificities as pre-
vious described , and antigen-specific ELISAs to MPO
and proteinase 3 were also used to detect sequential sera during
ELISA. Seven highly purifiedknown
Serum FT3, FT4 and thyrotropin were measured with chemolu-
minescence assay (Chiron Diagnostics ACS 180 Plus, MA, USA).
Organ involvement of PTU-induced AAV
Organ involvements such as lung, renal, neurologic and ENT
involvement and gastrointestinal vasculitis were determined by
biopsy or by well-defined clinical criteria [17, 18]. Systemic
involvement included fever, general malaise and weight loss.
Cutaneous disease was defined by a characteristic palpable
purpuric rash or urticaria  with or without ulcerations and/
or pathologically confirmed leucocytoclastic angiitis.
Definitions of organ involvement
Haematuria was graded as ‘gross’ or ‘positive’ (five or more red
blood cells per high-power field). Proteinuria was measured by the
pyrogallol red method and evaluated by 24h quantitative
measurement. The modified modification of diet in renal disease
equation in Chinese patients  or Schwartz equation  was
used to estimate glomerular filtration rate (eGFR) in patients
older or less than 18 yrs, respectively. End-stage renal disease
(ESRD) was defined when a patient required chronic maintenance
dialysis or renal transplantation. A euthyroid state was defined
when serum levels of FT3, FT4 and thyrotropin were within
Treatment protocols varied in patients and were drawn up in
Fig. 1. Treatment for patients with systemic symptoms only and
without lung or kidney involvement, was merely discontinuation
of PTU. Therapy for the patients with renal involvement
depended on the severity of clinical manifestation and histopatho-
logical lesions. Prednisone was given at an initial dose of 1mg/kg/
day for the first 4–8 weeks, followed by a gradually tapering dose
within 6–12 months. Cyclophosphamide (0.6–1.0g/month intra-
venously, or 1–2mg/kg/day orally) or mycophenolate mofetil
(1.5–2.0g/day) were administrated for 6–12 months. In addition,
patients with severe necrotizing crescentic GN and diffuse
pulmonary alveolar haemorrhage were also treated with pulse
methylprednisolone (7–15mg/kg/day) for 3 days, and patients
with life threatening massive pulmonary haemorrhage were
treated with plasmapheresis as well .
Treatment response [17, 18, 23] in patients with PTU-induced
AAV was defined as follows: remission was defined as stabiliza-
tion or improvement of renal function by calculated eGFR and
resolution of other manifestations of systemic vasculitis for >1
month , and it was further defined as complete remission and
partial remission. Complete remission was indicated by normal-
ization of renal function if renal insufficiency is existing and by
resolution of haematuria and extra-renal manifestations of
systemic vasculitis. Partial remission was defined by stabilization
or improvement of renal function or dialysis being independent if
renal insufficiency existed or by resolution of haematuria and
proteinuria and/or resolution of extra-renal manifestations of
systemic vasculitis. Treatment resistance was defined as progres-
sive decline in kidney function with persistence of active urine
sediment, or new or persisting extrarenal manifestations of
vasculitis despite immunosuppressive therapy. Relapse could
only occur in patients who reached remission and it was defined
as the reoccurrence of vasculitic signs or symptoms in any organ
Data were presented as mean? S.D., unless otherwise indicated.
Demographic characteristics of patients with PTU-induced
AAV on diagnosis
As shown in Table 1, 14 patients with PTU-induced AAV were
female and the other one was male with a mean age of 29.7?13.9
(9–57)yrs. All patients were diagnosed with Graves’ disease
originally. They were not overlapped with other connective tissue
diseases on diagnosis, and one patient had vitiligo for 20yrs.
Before diagnosis of vasculitis, PTU had been used continuously
except that one patient had restarted PTU due to relapse of
hyperthyroidism. The duration of PTU therapy before its with-
drawal was 48.0?25.8 (1.6–96) months and 14/15 (93.3%)
patients had received PTU for >24 months. The interval between
the occurrence of clinical vasculitis and the diagnosis of PTU-
induced AAV was 7.5?4.9 (1–18) months. Patients were followed
for 55.0?22.1 (25–98) months.
Clinical manifestations on diagnosis
The clinical data on diagnosis were shown in Table 2. Two
patients merely had systemic symptoms, 13/15 (86.7%) patients
P-ANCA was detected in sera from 14 (93.3%) patients and
C-ANCA in one. All sera recognized MPO and four sera also
recognized PR3. Antibodies directed against HLE, lactoferrin,
cathepsin G, azurocidin and BPI occurred in 7/14 (50%), 10/14
(71.4%), 9/14 (64.3%), 8/14 (57.1%) and 0/14 (0%), respectively,
and 13/14 (92.9%) recognized more than one target antigen.
As shown in Table 2, 14 (93.3%) patients had elevated ESR on
diagnosis. ANA was detected in sera from two patients (13.3%);
none of them had anti-dsDNA antibodies. Haematuria was
observed in all the 13 patients with renal involvement, seven
patients (53.8%) had gross haematuria. A 24h urine collection
showed pronounced proteinuria exceeding 3.5g/day, only in two
out of nine patients with proteinuria; both of them had acute renal
failure upon diagnosis. Decreased eGFR (50ml/min) was also
detected in another patient.
Histopathological manifestations on diagnosis
Renal biopsy was performed in 9 of the 13 (69.2%) patients with
renal involvement. Two were with focal segmental necrotizing
GN, three were with necrotizing crescentic GN and the other
four were with minor glomerular lesion. Immune complex was
found in five out of the nine patients (55.6%) with renal biopsy.
2 of 6Y. Gao et al.
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One patient who refused renal biopsy received skin biopsy, which
indicated early stage of pyoderma gangrenosum.
Treatment of vasculitis
As shown in Fig. 1, PTU was discontinued on diagnosis in all the
patients. The two patients without organ involvement did not
receive any further immunosuppressive therapy. Six patients with
haematuria and without renal insufficiency (three had minor
TABLE 1. The demographic data of the 15 patients with PTU-induced AAV on
No. Gender Age (yrs) Duration of PTU therapy (months)
F, female; M, male.
TABLE 2. The clinical data of the 15 patients with PTU-induced AAV on diagnosis
Clinical dataCases (n) Frequency (%)
Signs and symptoms
Elevation of ESR
Recognized more than one target antigen
Patients with PTU-induced ANCA-associated-vasculitis (n=15)
or with mild
crescentic GN on
renal biopsy (n=2)
or with diffuse
minor lesion on
renal biopsy (n=1)
(n=1) or focal
GN on renal
Patients with renal
Patients with both lung and renal
Ce, P Ce, P, MP,
Ce, P Ce, P
Ce, P, MP,
Patients without organ
GN on renal
Patients with organ involvement were divided
according to lung and renal involvement (n=13)
Ce, P, MP,
FIG. 1. The algorithm of treatment and outcome of the 15 patients with PTU-induced AAV. Ce: cessation of PTU; MP: methylprednisolone; P: prednisone; PE:
plasmapheresis; CR: complete remission; PR: partial remission.
Long-term outcomes of PTU-induced vasculitis 3 of 6
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lesion confirmed by renal biopsy, one received skin biopsy and the
other two refused biopsy) only received oral prednisone, but one
of the six patients refused to take prednisone further after 8 days.
Combined therapy with oral prednisone and immunosuppressant
was performed in one patient with diffuse pulmonary infiltrates
and renal involvement but without renal biopsy. Six patients with
severe necrotizing crescentic GN or focal segmental necrotizing
GN or diffuse pulmonary alveolar hemorrhage received pulse
methylprednisolone followed by combined oral prednisone and
immunosuppressant, one of them also had plasmapheresis due to
massive pulmonary haemorrhage. The duration of prednisone
administration and immunosuppressant therapy was 7.9?3.3
(0.27–12) months and 4.5?3.1 (2–9) months, respectively, except
that two patients received immunosuppressive therapy constantly
due to renal transplantation.
Treatment efficacy and long-term outcomes of vasculitis
Throughout the follow-up, 12 patients remained in complete
remission, one patient achieved and remained in partial remission,
and the decreased eGFR was stable and haematuria still existed at
the latest follow-up. Two patients were treatment resistant due to
late withdrawal of PTU because of unawareness of PTU-induced
AAV; both of them progressed to ESRD, and received dialysis
and further renal transplantation.
After withdrawal of PTU, the non-specific signs and symptoms
improved rapidly during the first week. Haematuria in one patient
with normal renal function relieved only after cessation of PTU
and an 8-day prednisone therapy. The mean duration for
resolution of haematuria was 12.1?13.1 (2–48) months. The
initial eGFR in the two patients with ESRD was <5ml/min, and
>80% of glomeruli had fibrous or fibrocellular crescent formation
in their renal histopathology.
All the 15 patients were followed up for a mean of 55.0 (25–98)
months. No relapse of vasculitis occurred even after discontinua-
tion of immunosuppressive therapy during follow-up.
Changes in ANCA levels during follow-up
For majority of patients with PTU-induced AAV, their ANCA
levels declined gradually but sera ANCA remained positive in 11
patients for a long time, despite quiescence of clinical symptoms.
ANCA turning negative only occurred in four patients (26.7%),
and the duration between the start of treatment and ANCA
turning negative was 24.8?18.2 (3–45) months.
Treatments and long-term outcomes of hyperthyroidism
For nine patients with uncontrolled hyperthyroidism on diagnosis
of PTU-induced AAV, six were switched to methimazole (MMI),
one patient received subtotal thyroidectomy and the other two
were treated with radioactive iodine. The other six patients had no
further anti-thyroid treatment initially due to euthyroid state.
During follow-up, one out of the six patients with MMI
therapy and one patient without any further anti-thyroid therapy
at presentation experienced relapse of hyperthyroidism and then
changed to radioiodine therapy. As shown in Table 3, at the latest
follow-up, seven patients were euthyroid and five had hypothy-
roidism. Three patients remained to have mild hyperthyroidism or
Interestingly, none of the patients with further MMI treatment
had relapse of vasculitis during follow-up.
The clinical manifestations of PTU-induced AAV are similar to
those of other idiopathic vasculitides, which ranged from systemic
manifestations to life-threatening multisystem vasculitis. In our
study, the duration of drug exposure in majority patients (93.3%)
was longer than 24 months; we speculated that longer treatments
might be a risk factor for PTU-induced AAV . Relapse of
hyperthyroidism was reported as another risk factor ;
however, we did not observe the similar phenomenon.
There are no unique clinically pathological or laboratory
aspects of drug-induced vasculitis that help to differentiate it from
other vasculitides . In our previous studies, it had been shown
that antibodies against multiple ANCA-specific antigens, espe-
cially the antigens rather than MPO and PR3, might be the
characteristic of drug-induced ANCA, which might be helpful to
discriminate it from primary AAV . In the current study, 13/14
sera recognized more than one target antigen.
Our follow-up data were encouraging. None of our patients
experienced relapse of vasculitis for a mean of 55.0 (25–98)
months even after discontinuation of immunosuppressive therapy.
It was quite different from the long-term outcomes of patients
with primary AAV, because ?11–57% of patients with primary
AAV had a relapse after achieving remission .
Since the mechanism of PTU-induced AAV was different from
that of primary vasculitis, the cornerstone of treatment for
primary AAV, including induction therapy might not be suitable
for all the patients with PTU-induced vasculitis . It had been
suggested that PTU was an important factor involved in the
pathogenesis and it might be involved in the production of ANCA
; therefore, cessation of PTU was essential in treatment for all
the patients, and it might be also enough for those with non-
specific systemic symptoms. However, in our previous study, one
patient failed to withdraw PTU in time on diagnosis, his renal
function deteriorated rapidly and he progressed to ESRD
eventually . It suggested that continued administration of
PTU might be associated with a poor prognosis in patients with
PTU-induced AAV. Nearly half (6/15) of the patients in our study
had non-specific systemic symptoms preceding organ involve-
ment. As Morita et al.  had suggested more severe specific
organ involvement might develop in patients with non-specific
systemic syndrome when PTU treatment was not withdrawn in
time. Therefore, it is reasonable to recommend that PTU should
be discontinued immediately after diagnosis of PTU-induced
In some case reports, organ involvement could also resolve in
patients only after discontinuation of PTU. However, in another
case report vasculitis worsened in the next 5 months after
cessation of PTU . Furthermore, in the literature, it was
reported that at least five patients died of PTU-induced AAV in
spite of intensive immunosuppressive therapy [9, 29]. Our data
supported the notion that the appropriate treatment for PTU-
induced AAV should be drawn up according to disease severity.
We suggested that in patients with severe and active organ
involvements, intensive immunosuppressive therapy such as
corticosteroid and immunosuppressive agents should be admin-
istrated to improve organ function and to prevent progression to
severe, irreversible disease. However, in spite of intensive therapy,
renal function did not return to normal range in two patients with
late crescentic GN in our study. As Gunton et al.  had
mentioned if necrotizing crescentic GN was present, the patients
were at high risk of developing chronic renal failure.
TABLE 3. Treatment and outcome of hyperthyroidism in patients with PTU-induced
AAV at the latest follow-up
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Up to now, no clear-cut decisions have been reached on how
long is the optimal period of immunosuppressive therapy and
whether long-term maintenance therapy for patients with PTU-
induced vasculitis is needed. In Fujieda’s report, although none of
the seven Japanese children had relapse of PTU-induced AAV
after immunosuppressive therapy, the mean duration of predni-
solone administration was 32?24 (range 1.0–60) months .
Helfgott and Smith  had speculated that PTU-induced AAV
was self-limited and that eventually all immunosuppressive
therapy could be discontinued. Our current study supported this
speculation. In our study, all the patients with organ-specific
involvement, except two patients with renal transplantation could
discontinue immunosuppressive therapy within 12 months suc-
cessfully; more importantly, no relapse was observed during
subsequent follow-up of 45.1 months. Our experience suggested
that the duration of immunosuppressive therapy in patients with
PTU-induced vasculitis could be much shorter than those with
primary AAV, as long as PTU was withdrawn, and further
maintenance therapy might not be necessary in PTU-induced
AAV. In fact, we have another four patients with PTU-induced
AAV with renal involvement (data were not shown). After
withdrawal of PTU and immunosuppressive therapy for 6–12
months, they all remained complete remission during follow-up
for 12–24 months.
Although ANCA is an important serological marker for certain
small vessel vasculitides, it might not be suitable for monitoring
the disease activity of PTU-induced AAV. After discontinuation
of PTU, even after immunosuppressive therapy, only 26.7% sera
of our patients with PTU-induced AAV turned to MPO-ANCA
negative despite clinical quiescence during follow-up. Actually,
serum ANCA still remained positive in majority of our patients in
complete remission for a long time up to 5 years. It has been
reported that ANCA remained positive for >30 months in five
children with PTU-induced AAV, and it did not turn to negative
during follow-up of ?100 months in one patient . Our previous
study had shown that although the levels of MPO-ANCA
decreased slowly, the other immunological characteristics of
MPO-ANCA might change substantially. For example, the
avidity of MPO-ANCA could decrease rapidly during follow-up,
indicating that the avidity of anti-MPO antibody could be used as
a more sensitive serological biomarker to reflect disease activity
. Furthermore, the levels of IgG4 subclass of MPO-ANCA
decreased dramatically after cessation of PTU, indicating that the
production of PTU-induced MPO-ANCA might be a result of
chronic antigen (PTU) stimulation . Other laboratory para-
meters such as ESR, which was associated with Birmingham
vasculitis activity score in our previous study , might be better
indicators for disease activity than the titres of ANCA.
During follow-up, microscopic haematuria remained positive in
one patient with partial remission, though other laboratory
parameters were all in normal range. It might be due to an
underlying renal disease. Immune complex was found in renal
histopathology in five out of the nine patients with renal biopsy in
our study, which indicated that PTU-induced AAV may co-exist
with other common primary renal disease .
For the treatment of hyperthyroidism, as most patients had
received PTU therapy over 24 months, which was longer than
recommendation in routine practice of anti-thyroid drug in
Graves’ disease , it might indicate more severe immunological
disorders of underlying thyroid disease in these patients. We
recommend that the treatments such as subtotal thyroidectomy or
therapy for those with long-term PTU treatment. PTU and MMI
are thioureylene derivatives, although possible cross-sensitivity
due to structural similarities had been suggested and there were
also several reports, in the literatures, on MMI-induced AAV, no
relapse of vasculitis had been observed in the current study after
switching PTU to MMI. Therefore, we recommended that MMI
131I should be taken into consideration in further
might be used as a substitution of PTU if necessary in those
refusing to surgical intervention and radiation.
In our patients, the systemic symptoms were always ahead of or
simultaneously with severe organ involvement, and patients
with severe renal insufficiency could not achieve complete
remission if PTU was not withdrawn in time. Based on these
findings, we recommended that patients with PTU treatment
should be monitored carefully during follow-up, especially those
taking PTU for >2 yrs in order to diagnose PTU-induced AAV
earlier. PTU should be discontinued immediately after diagnosis
of PTU-induced AAV and appropriate immunosuppressive
therapy, according to disease severity, should be administrated
only for patients with vital organ involvement, such as lung and
kidney vasculitis, in order to prevent progression to severe,
irreversible disease. Furthermore, the immunosuppressive therapy
might only last for 6–12 months without further maintenance
Funding: This study was supported by National natural science
foundation of China (No.30500459) and Beijing Natural Science
Disclosure statement: The authors have declared no conflicts of
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? Immunosuppressive therapy may be administered only for
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? Maintenance therapy might not be necessary.
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