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clinmed/2004110001v1 (February 28, 2005)
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USAGE OF ILOPROST IN  VASCULO-BEHÇET’S DISEASE

Case Report and Literature Review

 

Murat Ozeren, M.D.1, S.Pelin Kartal Durmazlar, MD,Ertan Yucel, M.D. 3

 

Mersin University Medical Faculty, Cardiovascular Surgery Department, , Mersin, Turkey.

Ankara Training  Hospital Social Security Organization (S.S.K), Dermatology2 and Cardiovascular Surgery3 Departments, Ankara, Turkey.

Corresponding author:     Murat Özeren, MD

 

Tıp Fakültesi Hastanesi

Zeytinlibahçe caddesi

33079, Mersin,TURKEY

Telephone:                                   +90-324-3374300/1240

Fax:                                              +90-324-3374305

E-mail:                                            mozeren{at}yahoo.com

Abstract

Background: Vasculo-Behçet’s disease is a rare but serious form of the disease and carries a poor prognosis. Here we are presenting first time successful results of iloprost in a VBD to prevent the patient from the catastrophic results of surgery.

Patient and method: A 34 year old male patient  with arterial involvement due to Vasculo-Behçet’s disease was hospitalized. Iloprost treatment was planned  to the patient because of his previous vascular operations and high recurrence rate of surgery in Behçet’s disease.

Conclusion: Iloprost is a safe and promising drug for the treatment of Vasculo-Behçet’s disease with arterial involvement and also we are recommending that iloprost can be used as an alternative first line medical treatment.

Key Words: Behçet’s Disease, Vasculitis, Prostanoids, prostocylin,Iloprost

 

 

 

 

Introduction

Behçet’s Disease (BD) is an inflammatory disorder characterized by recurrent oral apthous ulcers, genital ulcers, uveitis and skin lesions1. BD  associated with vascular lesions (vasculo-Behçet’s disease) is a rare but serious form of the disease and carries a poor prognosis2,3.  The surgical results were not satisfactory because of progressive graft thrombosis and formation of new aneurysms at the anastomosis, so surgical intervention is indicated only in patients with a growing arterial aneurysm, acute rupture or severe ischemia 2

Vascular injuries, hyperfunction of neutrophilis, and autoimmune responses are characteristics of BD in the etiopathogenesis.  The vascular injuries are superimposed on the hypercoagulability that is also characteristic of BD and that may be due in part to activated endothelial cells and activated platelets 4.

Medical or surgical management of patients with Vasculo-Behçet disease (VBD)  is still major problem and there is no consensus. As an alternative treatment to VBD with arterial involvement, we are prospecting iloprost, a synthetic stable prostacylin analogue, that the efficiency in patients with critical limb ischemia in terms of relief from rest pain, evidence of ulcer healing and lowered amputation rate have been proven in different studies 5,6

Prostacyclin and its analogues have been shown to act beneficially on activated platelets7, activated leucocytes8, leucocyte-vessel interaction9, and damaged endothelium improving microvascular perfusion 10. We thought that beneficial effects of ilomedin and etiopathogenesis of BD are overlapping in some aspects.

Here we are presenting successful usage of iloprost in a VBD patient with an extensive arterial involvement  first time in the literature and reviewing the effects of prostanoids in BD.

Case Report

           A 34 year old male patient  suffering from rest pain on his left leg for three months was hospitalized. In his past history; he had the diagnosis of Behçet’s disease based on oral and genital ulcers accompanied by relapsing iridocyclitis ten years ago. In his past history, he had the operations  for right femoral artery true aneurysm in 1999 and left femoral artery true aneurysm repair in 2000 and coronary artery aneurysms in 2003. Physical examination of the cardiovascular system revealed the absence of left femoral, popliteal and distal pulses and bilaterally chronic deep venous thrombosis.  Patient was afebrile  pulse rate was 78 per minute and  blood pressure was 110/70 mm Hg.  The chest roentgenogram showed mild cardiomegaly. Electrocardiogram demonstrated ST-T changings in the inferior and the lateral derivations. Transthoracic echocardiogram showed moderately diminished ventricular function of anterolateral wall. His laboratory tests were in normal in range. Peripheral Doppler ultrasonography showed obliterated left ilac artery and diminished velocity of distal arterial tree.  Magnetic resonance  angiography showing occluded left iliac artery and visualization of Left profunda femoris, superficial femoral and popliteal artery with the collateral circulation  (Figure 1 a-b). Iloprost treatment was planned to the patient because of his previous vascular operations and high recurrence rate.

Variables

Distance of claudication, ankle brachial index, dupplex ultrasonographic measurement of left anterior and posterior tibial artery, Fontain classification, hematologic variables (sedimentation rate, CRP, trombocyte, leucoyte, prothrombin time, activated partial thromboplastin time and bleeding time) are recorded before the treatment and same day of the week during the treatment.

Protocol

After giving the patient informed consent, one ml of iloprost (Ilomedin® 20 Schering AG) was diluted in 500 ml isotonic saline solution. Infusion of iloprost was started intravenously via superficial forearm vein at rate of 0.5 ng/kg/min per min and gradually increased during the 3 days in steps of 0.25 ng/kg to a maximum tolerated dose or up to 2.0 ng/kg per min. The optimum dose was continued up to a maximum of 8 hours, but was stopped earlier if the patient complained of any discomfort such as headache, flushing or nausea. The daily dose was reduced again in cases of adverse events. Infusion were given either daily with out any break and continued 6 weeks.

Results

Blood sedimentation rates (mean:23.42±1,27), CRP (mean 88.2±0.81), thrombocyte (mean:187142.9± 10965,3) and leucocyte counts (mean: 10771.43±917), prothrombin time (mean: 9.7±0.89), activated partial thromboplastin time (mean: 22.7±4.29) and bleeding time (mean:5.57±1.9) did not change  before and  after the infusion. Clinical evaluation of patient was satisfactory as shown in table I but this progression did not reflect to the blood flow of left extremity (Table 2)

DISCUSSION

Aeitology of vascular involvement.

The etiopathogenesis of BD remain poorly understood. It seems likely that the enhanced inflammatory responsiveness and vascular endothelial dysfunction that characterize the condition are triggered by immunological insults 11.  An interaction of an exogenous agent with the mononuclear cells may result in damage and/or vascular wall and  a tendency to thrombosis. These include impaired prostacylin synthesis by vessel walls 12, significantly higher levels of plasma endothelin-1,2, von Willebrand factor, and anti-endothelial cell antibodies 13. The role of thrombophilic parameters such as protein C, protein S and antithrombin deficiencies, antiphospholipid antibodies and factor V leiden have been analysed in BD with conflicting results 14,15,16.

Clinic manifestations of Vasculo-Behçet Disease

VB disease is divided into 3 groups have been divided into 3 groups (i) venous occlusion, (ii) arterial occlusion, (iii) aneurysm formation. Venous involvement was found in 33% of patients with BD (2). Prevalence of arterial involvement in VBD varies from 1.5% to 7% different series all over the world 2,3. Existence of arterial involvement is an indication of poor prognosis and life threatening complications2.  Starting with the aorta, the entire arterial tree can be affected. Peripheral arterial thrombosis may cause ischemic symptoms, intermittent claudication, and sometimes frank gangrene. Occlusion of the coronary, subclavian and carotid arteries can lead to myocardial infarction17, pulseless disease, and stroke respectively 18. This case was demonstrate femoral artery aneurysm and occlusion  with claudication.

Management

BD has an episodic nature, and relapses seem to run their course despite medical treatment. Different medical protocols are proposed ranging from platelet anti-aggregating drugs to anticoagulants in VBD. Therefore, the most common approach is the use of immunosuppressive agents such as corticosteroids, cytotoxic agents, and cyclosporine 19.

There is only one clinical study regarding usage of prostaglandins in VBD that Takeuchi and Hashimato obtained promising results for leg ulcers in BD with the oral prostaglandin E1 20. Gurer MA et al found that colchicine therapy is decreasing PGE2 and leukotriene C4 levels of BD. This decrease of PGE2 and leuktriene C4 results in inhibition of inflammation and polymorphonuclear leukocyte  by inhibiting the cyclooxygenase and lipooxygenase pathways21.  As a new treatment options, interferons  and tumor necrosis factor-α inhibitors seem to be effective in the management of ocular and extraocular manifestations of BD 22, but there is no data regarding treatment of VBD.

Our case was taking corticosteroid and cyclosporine as immunosuppressive, if we criticize this medication, corticosteroids may decrease the synthesis of prostaglandins.

The first treatment options for patients severe peripheral arterial occlusive disease are surgical bypass or percutaneous catheter procedures. Although these interventions have become more and more sophisticated, they are not the first choice in patients with VBD  because of the pseudo aneurysm formation, progressive graft thrombosis and formation of new aneurysms at the anastomosis 2.

The results of this  case shows that  6 weeks intravenous infusion of iloprost provided  satisfactory clinical status because of the reasons; increased distance of claudication, increased pulse oxygen saturation, decrease in the level of Fontain classification and limited increase in the velocity of anterior tibial artery.

In conclusion; Our findings  in this case  indicate that iloprost is a safe and promising drug for the treatment of VB with arterial involvement. We are also recommending that iloprost can be an alternative first line medical treatment in VB to prevent them from catastrophic results of the surgery, if the patient did not have an emergency clinical status such as acute ischemia. It is speculative to discuss beneficial effects of iloprost in BD. Further studies are mandatory to investigate hematological effects of iloprost in Behçet’s disease.

References

[1] Behçet H. Über rezidivierende, aphtöse, durch ein virus verursachte Geshwüre am Mund am Auge und an den Genitalien. Dermatol Wochensch 1937;105:1152-1157.

[2] Ozeren M, Mavıoglu I, Dogan OV, Yucel E. Reoperation results of arterial involvement in Behçet’s disease. Eur J Vasc Endovasc Surg 2000;20: 512-516.

[3] Saba D, Saricaoğlu, Bayram AS,et al. Arterial lesions in Behçet’s disease. VASA 2003;32:75-81.

[4] Ehrlich GE. Vasculitis in Behçet’s disease. Int Rev Immunol 1997;14:81-8.

[5] Cirillo G, Cucinoita D, Angelina A. Peripheral hemodynamic effects of intravenous infusion of a PGI2  analogue (iloprost) in elderly patients with severe peripheral arterial occlusive disease. Ather Cardiovasc Disease 1989;4:115-121.

[6] UK Severe Limp Ischemia group. Treatment of limp threating ischemia with intravenous iloprost: a randomized double-blind placebo controlled study. Eur J vasc Surg 1991:5:511-516

[7] Damaschino A, Evangelista V, Rajtar G, Chen ZM, Cerletti C, Gaetano G. Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents. Am J Physiol 1990:258:870-879.

[8] Belch JJF, Sanibaldi AR, Forbes CD. Whole blood white cell aggregation: a novel technique. Thromb Res 1987:48:631-639.

[9] Turker RK, Demirel E. Iloprost maintains acethylcholine relaxations of  isolated rabbit aortic strips submitted to hypoxia. Pharmacology 1988:36:151-155.

[10] Yazıcı H. The vasculitis:Behçet’s syndrome. In:Klippel JH. Dieppe PA (eds) Rheumatology. Mosby Year Book-Europe 1994:section 6:20:1-6.

 [11] Pickering MC and Haskard DO. Behçet’s syndrome. JR Coll Physicians Lond 2000,34.169-77.

[12] Kansu E, Sahin G, Sahin F, Sivri B, Sayek I, Batman F Impaired prostacyclin synthesis by vessel walls in Behcet's disease. Lancet.  1986 15;2:1154

[13] Cervera R, Navarro M, Lopez-Soto A, et al. Antibodies to endothelial cells in Behçet’s disease:cell binding heterogenity and association with clinical activity. Ann Rheum Dis 1994;53:265-7.

 [14] Salvarini C, Calamia K, Silingardi M, et al: Thrombosis associated with the trombin G"A20210 mutation in Behçet’s disease. J Rheumatol 2000,27:515-516.

[15] Gul A, Inanc M, Ocal L, et al. Familial aggregation of Behçet’s in Turkey. Ann Rheum Dis 2000,59:622-625.

[16] Ehrlich GE.Vasculitis in Behçet’s disease. Int Rev Immunol 1997;14:81-8.

[17] Ozeren M, Dogan OV, Dogan S, Yucel E. True and pseudo aneurysms of coronary arteries in a patient with Behçet’s disease. Eur J Cardiothorac Surg   2004 ;25:465-467.

[18] Wechsler B, Du LT, Kieffer E. Cardiovascular manifestations of Behçet’s disease [Review]. Blood Coagul Fibrinolysis 2000;11:107-10.

 [19] Kaklamani VG, Kaklamanis PG. Treatment of Behçet’s Disease-An update. Semin Arthritis Rheum 2001;30:299-312

[20] Takeuchi A, Hashimoto T. Oral prostaglandin E1 as a therapeutic modality for leg ulcers in Behcet's disease. Int J Clin Pharmacol Res.  1987;7:283-9. 
[21]  Gurer MA, Keskin N, Gulekon A, Karel L, Aksakal B, Baysal V. Arachidonic acid metabolites and colchicine in Behcet's disease (BD). Prostaglandins Leukot Essent Fatty Acids.  1991 Aug;43(4):257-9.  
[22] Arayssi T, Hamdan A. New insights into the pathogenesis and theraphy of Behçet’s disease. Current Opinon in Pharmacology 2004;4:183-188.

 

Figure legends

Figure 1a-b: Magnetic resonance  angiography showing occluded left iliac artery and visualization of Left profunda femoris, superficial femoral and popliteal artery with the collateral circulation.

 

 

 

 

 

Table 1: Clinical evaluation of patient

 

Pre-infusion

1.Week

2.Week

3.Week

4.Week

5.Week

6. Week

Distance of claudication

20 m

20 m

30 m

50 m

80 m

90 m

100 m

Ankle brachial index  of left foot

0.5

0.5

0.5

0.6

0.6

0.7

0.7

Fontain class

III

III

IIb

IIb

IIb

IIa

IIa

 

 

 

 

 

Table 2: Progression of blood velocity measured from left anterior and posterior tibial artery

 

 

 

 





This Article
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Right arrow Download to citation manager
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Right arrow Articles by Ozeren, M.
Right arrow Articles by Yucel, E.
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Right arrow Articles by Ozeren, M.
Right arrow Articles by Yucel, E.
Related Collections
Right arrow Cardiovascular Medicine:
Other Cardiovascular Medicine


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