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: a_dellarossa{at}hotmail.com

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{alpha} 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{gamma}{delta} 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-{alpha} [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

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Accepted 21 March 2005





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