Rheumatology Advance Access originally published online on

April 19, 2005

Rheumatology 2005 44(8):1074-1075;
doi:10.1093/rheumatology/keh661
© The Author 2005. Published by Oxford University Press on behalf
of the British Society for Rheumatology. All rights reserved. For
Permissions, please email: journals.permissions@oupjournals.org

LETTER TO THE EDITOR

Two Takayasu arteritis patients

successfully treated with infliximab:
a potential disease-modifying
agent?
A. Della Rossa, A. Tavoni1, G. Merlini1, C. Baldini, M.
Sebastiani, M. Lombardi2, D. Neglia2 and S.
Bombardieri
Rheumatology Unit and 1 Immunology Unit, Department of Internal
Medicine, University of Pisa and 2 CNR Institute of Clinical
Physiology, Pisa, Italy.
Correspondence to: A. Della Rossa, Rheumatology Unit, University of
Pisa, Via Roma 67, 56126, Pisa, Italy. E-mail:
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SIR, Takayasu arteritis (TA) is a chronic, idiopathic,
inflammatory disease that primarily affects large vessels
[1]. The management of this disorder is largely
unresolved, since a large number of patients fail to reach
stable remission on conventional treatment [2]. Thus, the
need for more efficacious medical therapies is paramount
in order to spare steroids and to prevent long-term
toxicity and reduce disease-related morbidity and
eventual mortality [3]. Recently, Hofmann et al. [4] have
claimed the safety and efficacy of anti-tumour necrosis
factor (TNF) therapy in an open label study in 15 patients
with TA. Here we present two more cases of Takayasu
arteritis treated with anti-TNF infliximab, in which
clinical remission was observed.
Two patients with TA were treated at the Immunology
and Rheumatology Units of the University of Pisa. The
diagnosis of TA was made on clinical grounds. The patients were classified as TA according to the
Sharma modified diagnostic criteria [5].
Patient 1 is a 23-yr-old, female. In January 2001 she experienced sudden onset of visual loss (amaurosis
fugax) and cluster headache, as well non-specific symptoms such as fever, arthralgias, weight loss,
malaise and weakness.
In October 2002 she had an abdominal CT scan, whole-body PET and angio-magnetic resonance
imaging (MRI) with signs of inflammation and narrowing of the distal thoracic aorta and of the
abdominal aorta beyond the origin of the renal arteries. There was narrowing of the left carotid artery
and elevated erythrocyte sedimentation rate (ESR: 81 mm first hour), C-reactive protein (CRP: 6.7
mg/dl) and fibrinogen (576 mg/dl).
Treatment consisted of three i.v. 6-methylprednisolone pulses and oral cyclophosphamide 100 mg daily.
There was resolution of systemic symptoms and normalization of inflammation indices. Steroid therapy
was gradually tapered (April 2003, final dose of 8 mg/day). Cyclophosphamide was reduced to 50
mg/day. Systemic symptoms recurred and the patient experienced neck pain and blurred vision. Serial
MRI confirmed narrowing of the left carotid artery and involvement of the aortic arch, close to its
origin. ESR was 56 mm first hour and CRP 4.8 mg/dl. Cyclophosphamide was stopped, and weekly
i.m. methotrexate (MTX) (up to 20 mg) started, with slight clinical improvement.
In September 2003 the symptoms recurred. An ultrasonogram with Doppler study showed narrowing of
the bilateral common carotid (70–80% narrowing of the lumen to the right and 60% to the left). Angio-
MRI study confirmed this involvement with stenosis of the right division involving the external carotid
artery in addition to the previous lesions as well as irregular narrowing and thickening of the left
vertebral artery in its origin and of the left subclavian artery.
In November 2003 infliximab 3 mg/kg was given at 0, 2, 4 and then every 8 weeks and MTX was
reduced to 15 mg weekly. The patient's systemic symptoms resolved 4 weeks after initiation of therapy
and her ESR returned to normal. Corticosteroids were gradually tapered and eventually stopped. After 8
months of follow-up (on maintenance therapy with infliximab 3 mg/kg every 8th week) the patient
remains in good clinical condition. Control colour Doppler shows no disease progression.
Patient 2 is a 16-yr-old female. In 1998 she experienced sudden onset of non-specific symptoms
including nausea, anorexia, weight loss, arthralgias and lumbar pain. Physical examination showed no
palpable pulse in the right arm.
In 1999 an ultrasonogram with Doppler study showed narrowing of the right common carotid and
stenosis of the right subclavian artery. Angio MRI showed: narrowing of the aortic lumen at the
diaphragmatic hiatus, thickening of the walls and luminal thrombosis; segmental stenosis and
thickening of the left internal carotid and of the left subclavian artery close to their origin; and stenosis
of the division of the anonymous artery.
There was elevation of inflammation indices (ESR 100 mm first hour; CRP 64 mg/dl; fibrinogen 682
mg/dl). Treatment consisted of azathioprine (AZA) 50 mg/day and small doses of methylprednisolone
(4–8 mg/day). The symptoms never resolved: AZA was discontinued in 2000; 6-methylprednisolone 1
mg/kg/day and i.v. cyclophosphamide (CPM) pulses were started (CPM 500 mg, 10 monthly pulses).
In June 2001 the patient was referred to our unit for the first time for the persistence of systemic
complaints, including fatigue, anorexia, weight loss, malaise, fever, lumbar pain and recurrent
abdominal pain. There was severe corticosteroid toxicity, with cushingoid appearance, striae rubrae and
reduced bone mass.
A colour Doppler study demonstrated progression of vascular lesions, with the addition of stenosis of
the coeliac trunk and of the superior mesenteric artery to the previous involvement. ESR was 38 mm
first hour and CRP and fibrinogen were in the normal range. The patient was on 6-methylprednisolone
1 mg/kg/day. In order to spare steroids and to obtain better control of the disease, oral CPM was added,
50 mg/day.
During gradual tapering of the corticosteroid dose (8 mg/day), systemic symptoms and abdominal pain
recurred. ESR was 32 mm first hour, CRP 2.2 mg/dl and fibrinogen 544 mg/dl. CPM was stopped, and
on June 2002 the patient started weekly i.m. MTX (10 mg). The patient remained stable until March
2003 when there was sudden onset of severe headache, pain and functional limitation to the right arm,
exertional dyspnoea as well non-specific symptoms including fever, weight loss and lumbar pain.
Angio-MRI showed progression of the vascular lesions; in addition to the previous lesions, severe
bilateral involvement and narrowing of the common carotid arteries (with 80% lumen narrowing). ESR
was 110 mm first hour, CRP 8.9 mg/dl and fibrinogen 696 mg/dl.
Infliximab 3 mg/kg was started at 0, 2, 4 and then every 8 weeks, along with MTX 15 mg/weekly. Her
clinical symptoms disappeared and inflammation indices returned to normal. Control colour Doppler
showed stabilization of the lesions. The patient remains stable and the steroids have been gradually
tapered until a final dose of 4 mg/day was reached in June 2004 (on maintenance therapy with
infliximab 3 mg/kg every 8th week).
Our patients had a good clinical response after infliximab therapy. Before the start of this treatment
they had a long history characterized by episodes of remission and relapse, always requiring the
administration of small to medium doses of steroids. The dosage of these drugs was never tapered
below the equivalent of 7.5 mg of prednisone per day. In addition, immunosuppressive drugs were
needed, with unremarkable results. We hypothesized that our patients might benefit from the use of the
anti-TNF agent infliximab, since Takayasu arteritis is considered to be a cell-mediated process [6]. In
this disease, infiltrating T cells, cytotoxic T lymphocytes and natural killer cells might directly
damage the arterial wall by releasing cytolytic factor. In analogy with rheumatoid arthritis, T cells
infiltrating the vessels walls might release strong pro-inflammatory cytokines, such as IL-6 and TNF-
[6–8].
We based the definition of disease remission on disappearance of all clinical and laboratory
manifestations in the setting of fixed vascular lesions demonstrated by non-invasive investigations
(such as angio-MRI or colour Doppler). The choice of these procedures instead of angiography, which
remains the gold standard [9], was motivated by the need for non-invasive investigations in severely ill,
immunocompromised patients [10].
Our patients achieved a remission of the disease and, more importantly, the steroid dosage was tapered
and finally discontinued in one patient. However, two points must be mentioned. First, since the natural
course of the disease is characterized by alternating periods of remission and relapse we cannot rule out
that our patients’ remissions were spontaneous and independent of anti-TNF therapy. The
discontinuation of steroid therapy is a pointer in favour of the beneficial effect of this treatment,
however.
Second, the definition of disease activity and remission is not universally accepted in this disease and a
substantial number of patients considered clinically to be in remission may have a smouldering, slow-
acting inflammatory process in biopsy specimens [2, 6]. We have no answer to this second point, since
we couldn’t obtain serial specimens for histology. Our patients had complete resolution of all clinical
features, as well as stabilized vascular lesions, and this was considered a success, since they were
treated with steroids for a long time and with ‘classical’ immunosuppressives without benefit.
In conclusion, our report indicates that anti-TNF treatment may prove useful both for disease control
and to avoid the risk of long-term toxicity of corticosteroids and classical immunosuppressive drugs in
Takayasu arteritis. Large multicentre, prospective studies are needed to confirm this preliminary
observation.
The authors have declared no conflicts of interest.
References
1. Nakao K, Ikeda M, Kimata S, Niitani H, Niyahara M. Takayasu's arteritis. Clinical report of
eighty-four cases and immunological studies of seven cases. Circulation 1967;35:1141–55.
[Abstract/Free Full Text]
2. Kerr GS, Hallahan CW, Giordano J et al. Takayasu arteritis. Ann Intern Med 1994;120:919–29.
[Abstract/Free Full Text]
3. Daina E, Schieppati A, Remuzzi G. Mycophenolate mofetil for the treatment of Takayasu
arteritis: report of three cases. Ann Intern Med 1999;130:422–6.[Abstract/Free Full Text]
4. Hoffman GS, Merkel PA, Brasington RD, Lenschow DJ, Liang P. Anti-tumor necrosis factor
therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum 2004;50:2296–304.
[CrossRef][Web of Science][Medline]
5. Sharma BK, Jain S, Suri S, Numano F. Diagnostic criteria for Takayasu arteritis. Int J Cardiol
1996;54:S141–S147.
6. Hotchi M. Pathological studies on Takayasu arteritis. Heart Vessels Suppl 1992;37:11–27.
7. Seko Y. Takayasu arteritis. Insight into immunopathology. Japan Heart J 2000;41:15–26.
8. Salvarani C, Cantini F, Boiardi L, Hunder GG. Laboratory investigations useful in giant cell
arteritis and Takayasu's arteritis. Clin Exp Rheumatol 2003;21(Suppl 32):S23–S28.
9. Parra JR, Perler B. Takayasu's disease. Semin Vasc Surg 2003;16:200–8.[Medline]
10.Seo P, Stone J. Large-vessel vasculitis. Arthritis Rheum 2004;51:128–39.[CrossRef][Web of
Science][Medline]
Accepted 21 March 2005
http://www.caringmedical.com/condition_details/
Takayasu_Arteritis.htm
CONDITION: Takayasu Arteritis
DESCRIPTION:
Takayasu arteritis is a rare form of the autoimmune disease known as vasculitis, which involves inflammation of the blood
vessels. In Takayasu arteritis the inflammation occurs in the blood vessels leading to the aorta and its branches, impairing
blood flow through the vessels and to the surrounding tissues. Takayasu arteritis is nine times more likely to afflict women
than men, particularly Asian women under the age of 40. Only 2 or 3 cases of the disease occur each year per million people in
a population.
How does Takayasu arteritis develop?
The cause of Takayasu arteritis is unknown. It is clear, however, that the immune system plays a critical role in the tissue
damage caused by the disease. The immune system produces antibodies that attack the body, causing inflammation to develop
in the blood vessels. Inflammation in blood vessel and artery walls leads to narrowing of the vessels. The blood vessels
become leaky or clogged, disrupting blood flow to nerves, organs and other parts of the body. Inadequate blood supply to a
particular tissue or organ can result in permanent damage such as loss of pulse points and pulmonary failure. Any organ or
combination of organs in the body can be affected.
What are the symptoms of Takayasu arteritis?
Symptoms of this disease can be divided into two phases: a systemic phase and an occlusive phase. In the systemic phase,
patients have symptoms that may include fever, fatigue, weight loss, osteoarthritis and non-specific aches and pains. There
may be tenderness of affected arteries. In the occlusive phase, patients begin to develop symptoms caused by the narrowing of
affected arteries, including pain in the limbs, dizziness, headaches and visual problems. During this phase, blood vessels may
narrow to such an extent that the normal pulses in the neck, elbow, wrist or lower extremities cannot be felt. High blood
pressure is common, but blood pressure taken in the arm may be read falsely as low if there is a narrowing artery in that
extremity. The pulmonary arteries may also be affected in this disorder.
Conventional medical treatments may help relieve the symptoms of Takayasu arteritis but they do not address the root of the
problem. Generally, by undergoing comprehensive natural medicine testing, the reasons the body is producing antibodies
against itself can be found. Some of these reasons include sensitivities or allergies to foods, inhalants and chemicals and
various infections.
Discover why we believe that natural medicine treatments are the best way to treat Takayasu arteritis.

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Treatment of Takayasu Arteritis:
The Response of Traditional Medicine
The immune system, which is a complex network of specialized
organs, cells and cell products, is continually making antibodies to
help rid the body of substances it sees as "non-self," such as
bacteria, viruses, infectious agents and even "worn out," damaged
or mutant cells. When the immune system identifies an infection or
allergen, it produces antibodies against the offending organism or
substance so it can be eliminated from the body. In autoimmune
diseases, the immune system fails to distinguish between "self" and
"nonself," and thus attacks the body's own vital organs, systems,
cells and tissues.

The list of autoimmune diseases is both long and disturbing. In

treating these diseases, traditional medical practitioners focus on relieving the symptoms and slowing the progression of the
diseases. The main allopathic treatment used for most autoimmune conditions is Prednisone (steroids). This approach, at
best, can just slow the progression of the disease. Used long-term, Prednisone can cause a host of problems, including
osteoporosis, immune suppression, weight gain, bloating, thin skin, easy bruising and many other troubling side effects.
Prednisone is used because it helps control symptoms; but it does not address the etiology of the underlying condition.

Caring Medical's Natural Medicine Approach to Autoimmune Diseases

In caring for patients, we look for the cause of the problem and recommend therapies that address the source of the disease.
This involves giving the body what it is missing and removing what is harmful.
Since autoimmune diseases are caused by autoantibodies, the question we ask is, "Why is this person making these
antibodies?" Most experts in the natural medicine field believe that many of these autoantibodies are produced by the body
in response to an infection or allergen. When the offending infection(s) or allergen(s) are removed, the production of these
destructive autoantibodies stops.

We developed what we call the Hauser Diet® Natural Medicine Program which we designed for the person who has a
chronic condition such as an autoimmune disease, and is ready to take a serious step in getting to the root cause of their
condition. Ross Hauser, MD and Marion Hauser, MS, RD have developed this program over years of experience in both the
traditional and natural medicine fields. There are three programs and each is priced as a package. As a New Patient, the
individual tests and consultations each play a significant role in the program. In other words, we use the minimum number
of tests that will tell us the maximum amount of information, to help you attain optimum health. That is what the Hauser
Diet® Natural Medicine Program is all about. Some individuals may require additional laboratory tests.

Why follow this program? Good Candidates for our Natural Medicine Program include patients who want to seriously
utilize the principles of the Hauser Diet®, are motivated to make necessary lifestyle modifications, are willing to start an
aggressive herbal program, and in some cases take natural hormone replacement, or do other natural medicine modalities as
needed.

For example, depending on the results of the testing, we may typically place our patients on allergy elimination diets to help
the body stop producing autoantibodies. Patients typically see an improvement in symptoms after following their allergy
free diet. Another avenue to pursue is to look for the presence of infection or other foreign invaders. Antibiotics are
administered for bacteria, antivirals for viruses, antifungals for fungus infections, depending on what the results of the
laboratory testing reveal.

A Final Note About the Immune System

We've noted the important role that the immune system plays in identifying and eliminating infectious cells in the body. It's
also important to highlight the critical role this system plays in eliminating abnormal or mutant cell types which may also
arise. This function, known as immune system surveillance, constitutes one of the body's major defenses against cancer.

Today's statistics show that one in three Americans will develop cancer in their lifetime. The body depends on a healthy,
well-functioning immune system to protect it from this devastating disease. Clearly, it is not enough to treat symptoms or
slow the progression of autoimmune diseases; it is essential to restore the immune system to a healthy state and prevent
against further damage and disease. And with natural medicine, this kind of healing is possible!

Read about one woman's tremendous success in treating her autoimmune disease with natural medicine. And find out how
natural medicine therapies reversed an agressive case of rheumatoid arthritis.

If you are interested in more information about our natural medicine program or to schedule an appointment with Dr.
Hauser, please contact Caring Medical at 708-848-7789 or online using our contact form.
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The treatment regimens suggested here are based on the experience Caring Medical. They do not apply to every case or
condition. A person using these recommendations without the aid of a personal physician does so at their own risk.

This information is provided for informational purposes only. It is essential to have your condition evaluated by your own
personal physician. For an appointment with Ross Hauser, M.D., please call 708-848-7789. or email us at
scheduling@caringmedical.com.