# Churg-Strauss Syndrome following PTU Treatment

Authors: R. A. M. Quax; A. J. G. Swaak; M. G. A. Baggen
Journal: International Journal of Rheumatology
 (2009)

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## Abstract

Propylthiouracil (PTU) is a frequently prescribed drug in the treatment
of hyperthyroidism. The use of PTU is, however, accompanied by numerous potentially
serious side effects including vasculitis. PTU-related vasculitides can present as
haematuria, pulmonary haemorrhage, or cutaneous lesion together with aspecific
symptoms such as fever, myalgia, arthralgia, and fatigue. Cerebral involvement is
seldom observed. We present a 49-year-old female with Graves' disease and
asthma, who developed paresis of the proximal extremities, eosinophilia, pulmonary, and cutaneous lesions following treatment with PTU. A cerebral vasculitis consistent with Churg-Strauss syndrome (CSS) was suspected. Although cerebral involvement is seldom observed with PTU treatment, cerebral vasculitis should be considered in patients developing CNS symptoms.


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## Body

## 1. Introduction

Numerous observations regarding the
detection of a positive ANCA in patients treated with PTU in Graves' disease
have been published [1–8]. The
determination of antineutrophil cytoplasmic antibodies (ANCAs) is a highly specific and sensitive marker for the so-called ANCA-associated vasculitis. Vasculitis is a
disease characterised by an inflammatory reaction in and around blood vessels. The vasculitides are classified on the basis of vessel size and the
inflammatory reaction pattern. Using indirect immunofluorescence techniques (IFTs), two patterns of
staining can be observed. Antiproteinase 3 (PR3) antibodies produce a
diffuse cytoplasm pattern of staining in the IFT (c-ANCA). The presence of
these antibodies is associated with Wegener’s granulomatosis. A perinuclear
pattern of immunofluorescence staining (p-ANCA) is a characteristic for the
presence of anti-myeloperoxidase antibodies (MPO). These antibodies are linked
with microscopic polyangiitis, but can also be found in Wegener's disease and
Churg-Strauss syndrome. These diseases are taken together as ANCA-associated
vasculitides. The exact mechanisms underlying these ANCA-associated
vasculitides are unknown.PTU-induced ANCA-associated vasculitides
mainly relate to the renal, cutaneous, and pulmonary systems.We describe a patient with Graves’
hyperthyroidism, who developed a cerebral vasculitis consistent with
Churg-Strauss syndrome after treatment with propylthiouracil (PTU).


## 2. Case Report

In July 2004, a 49-year-old woman was admitted to the
Department of Internal Medicine with complaints of palpitations. Her past
medical history was asthma, allergic diathesis, hay fever, and vitiligo.
Laboratory examination demonstrated an elevated free T4 (30 pmol/L)
and low TSH (<0.01 mIU/L). Iodine-123 scintigraphyshowed diffuse
high uptake indicating Graves’ disease. Treatment was started with thiamazole
(30 mg per day). After two weeks of treatment with thiamazole, the patient
developed a pruritis, and thiamazole was replaced by propylthiouracil (PTU)
given in a dose of 100 mg three times a day. Levothyroxine was started at a
dose of 87.5 μg daily (block-and-replace therapy). Thereafter, she became
euthyroid.Five
months after the start of PTU treatment, she developed a progressive loss of
strength in her arms and legs. Her health deteriorated
further with complaints of a painful abdomen, diarrhoea, and diffuse pruritis
with skin rashes. Physical
examination upon admission to the hospital showed petechiae, neurodermatitis,
and nailfold lesions. A mild paresis of the proximal extremities was observed.
Laboratory tests demonstrated an eosinophilia (4780 eosinophils/μL and 44% eosinophils
on differential white blood cell count). Liver enzymes and creatinine
phosphokinase were normal. Serum creatinine was slightly elevated (111 μmol/L)
with an active urine sediment analysis showing traces of protein and
microhematuria.X-ray examination of the lungs revealed a
diffuse interstitial pattern consistent with interstitial pneumonitis. In the
following days, the patient developed fever and urticaria. Serological
investigation revealed the presence of a positive ANCA with a titre of 1:2048. Anti-MPO
(1:1280) and anti-PR3 (1:640) antibodies were also detected as measured by ELISA.
Screening assays for antinuclear antibodies (ANAs/ENA/dsDNA) and rheumatoid factors (anti-CCP)
were negative.  Other causes for a
vasculitis were excluded, like the presence of cryoglobulins or a hepatitis
(screening assays for Hepatitides B and C, CMV, EBV, and HIV were negative). A systemic vasculitis was considered
most likely. The differential diagnosis was of idiopathic hypereosinophilic
syndrome, eosinophilia-myalgia syndrome, or parasitic infection. Although PTU
was stopped immediately, there was progression of the neurological symptoms.
She became totally bedridden due to progressive loss of strength of the
proximal extremities. She also developed signs consistent with peripheral
sensory polyneuropathy. The symptoms were more pronounced on the left side.
Furthermore, and so far unnoticed, she demonstrated a positive Babinski sign on
both sides. Cerebral magnetic resonance imaging revealed lesions in the parietal
regions compatible with recent infarctions. Other causes of her fever and
diarrhoea were excluded.Under
suspicion of a generalised vasculitis with cerebral extension, the patient was
treated with methylprednisolone (1000 mg/d) for three days, and
cyclophosphamide (15 mg/kg iv.) was started at four weeks time intervals. After
3 days, the methylprednisolone was changed in prednisolone (1 mg/kg/d). Under
this treatment regime, neurological symptoms diminished rapidly, and the
clinical signs of vasculitis including the nailfold lesions, skin rash,
urticaria, and pruritis disappeared. Three weeks after onset of treatment, the
ANCA titre was decreased to 1:1024. At that moment, laboratory values were all
normalised. The ANCA titre further decreased to 1:64 after three months and
became negative after 1 year until now.We
classified our patient as Churg-Strauss syndrome with cerebral involvement
induced by the use of propylthiouracil (see Table1).Table 1
Criteria
for the classification of Churg-Strauss syndrome (CSS). The presence of four or
more of these criteria yields a sensitivity of 85% and a specificity of 99.7%
for CSS according to the American College of Rheumatology (ACR).
ACR criteriaPresent in our patientAsthmaYesEosinophilia
>10% on differential white blood cell countYesMononeuropathy
or polyneuropathyYesMigratory or
transient pulmonary opacities detected radiographicallyYesParanasal
sinus abnormalitiesNoBiopsy
containing a blood vessel showing the accumulation of eosinophils in
extravascular areas—Two years after initial presentation, she is
in clinical good condition using 7.5 mg prednisone and 150 mg azathioprine
daily.


## 3. Discussion

The development of ANCA following treatment
with antithyroid medication has been described numerous times. In a large
cross-sectional study [2] (n=407), a high prevalence of a positive ANCA
was described in patients with Graves’ disease using antithyroid drugs as
compared with euthyroid controls. In patients with Hashimoto’s disease, there
was no significant higher prevalence of ANCA. Moreover, the development
of a positive ANCA was associated with propylthiouracil usage to a greater
extent than with carbimazole, highlighting that the autoimmune disease itself
is not (fully) responsible for the development of ANCA. In a small cross-sectional study [3] (n=30), 27% of patients on long-term antithyroid medication were ANCA
positive. These results were also confirmed in another retrospective study [4];
anti-MPO antibodies were detected in 25% of the patients treated with PTU, but
only 3% of the patients treated with thiamazole. Data about the prevalence of a
positive ANCA in patients with hyperthyroidism before the start of the
treatment are scarce. In two of these studies [5, 6], the close
relationship between the treatment with PTU and development of ANCA could be
established. No correlation was detected between treatment with methimazole and
ANCA positivity. A positive ANCA could only be demonstrated in the PTU treated
patients. In children with Graves’ disease, anti-MPO antibodies were found in
7% of patients before treatment. Of those patients treated with PTU, 64%
developed anti-MPO antibodies (mean duration of PTU treatment 4.0±3.6 yr)
while none of the patients treated with thiamazole developed autoantibodies [7].
These cited observations strongly suggest that antithyroid treatment,
specifically PTU, is associated with the development of ANCA.However, an important question to solve is
whether every patient who develops these kinds of antibodies will also develop
an ANCA associated vasculitis.Most of the literature concerning
PTU-induced ANCA-associated vasculitides has been published as case reports.
After the first publication by Dolman et al. [8] in 1993, numerous case
reports of PTU-induced vasculitis have been described, with a wide spectrum of
clinical presentation (see Table 2).Table 2
Most frequent observed clinical
symptoms in PTU-induced ANCA-associated vasculitis. In total,
61 well-described patients were studied.
SyndromeFrequencyPercentage (%)Renal involvement4472Fever2643Arthralgia2236Pulmonary involvement1626Cutaneous lesions1423Myalgia1118Eye involvement711Pericardial effusion23Central nervous system12Renal involvement is mostly characterised by
haematuria, proteinuria, or oliguria [9–25]. Renal
biopsies showed two patterns, either pauci-immune necrotizing
glomerulonephritis or pauci-immune crescentic glomerulonephritis.Skin involvement as a cutaneous
ANCA-associated vasculitis has been reported several times, with clinical signs
as purpura, ulcerating skin, and erythematous lesions [8, 11, 14, 15, 18, 22, 26–30]. Skin
biopsy mostly revealed the picture of a leucocytoclastic vasculitis
[27, 28].Pulmonary involvement is highly prevalent,
although only one case was proven histologically [10]. In two other
reports, lung biopsy only confirmed the presence of hemosiderin filled
macrophages [20, 31]. Nevertheless, as dyspnoea, haemoptysis, or respiratory
failure clearly improved on withdrawal of PTU or were directly correlated with
histological proven vasculitis elsewhere, these clinical features are strongly
indicative of pulmonary vasculitis [9, 10, 13, 17, 20–23, 25, 26, 31].
Other frequently observed symptoms are arthralgia, fever, myalgia, and
scleritis.To our knowledge, no literature is known
about the use of antithyroid drugs and development of CSS. Even more so, the presence of eosinophilia is never mentioned in
previous reports.Recently, the first patient with a cerebral
vasculitis following PTU treatment was described [1]. In contrast with
our case report, this patient was only MPO-ANCA positive. Our patient developed
central nervous system symptoms after using PTU for six months (versus 3 years
in the other patient). The neurological symptoms of our patient consisted of a
progressive loss of muscle strength, positive Babinski signs, and a sensory
polyneuropathy, whereas the neurological symptoms of the other patient
consisted of cognitive deficits. Signs of recent cerebral infarction were
present in our patient. In both patients, the outcome improved after
discontinuation of the PTU and the start of immunosuppressive therapy.Despite accumulating reports demonstrating
ANCA-associated vasculitis following treatment with antithyroid drugs, most
ANCA-positive patients do not have clinical manifestations of vasculitis [2–7]. This
discrepancy suggests that other factors are of importance in the development of
vasculitis besides ANCA positivity.Patients developing PTU-induced
ANCA-associated vasculitis have been shown to have a significant higher titre
and affinity of anti-MPO antibodies as compared with ANCA-positive patients
without developing vasculitis [21]. Gao and coworkers found
significantly decreased affinity and/or titre of anti-MPO antibodies after
cessation of PTU and initiation of immunosuppressive therapy in patients with
PTU-induced ANCA-associated vasculitis [22, 32]. Therefore, the titre
and affinity of anti-MPO antibodies might be clinical markers for the
development of PTU-induced ANCA-associated vasculitis.Further research
is needed to establish this association.


## 4. Conclusion

Antithyroid drugs, especially PTU, are
associated with the development of ANCA. Not every patient developing ANCA will
develop a vasculitis, given the discrepancy between the prevalence of
PTU-induced ANCA and clinically evident vasculitis. Consequently, screening of
patients using PTU is not recommended. Further research is needed to asses if
titre and affinity of anti-MPO antibodies can be used to predict the risk of
developing vasculitis following treatment with antithyroid drugs. Patients
using antithyroid drugs in general and PTU in particular should be closely
monitored for signs of vasculitis, including central nervous system symptoms.



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