Pentoxifylline is a membrane fluidizer that modulates receptor-mediated cellular functions [1]. It also modulates neutrophil motility, suppresses production of superoxide anion (O_2–), and reduces neutrophil-induced tissue damage [1, 2].

We examined the effect of pentoxifylline in controlling Behcet disease. We administered 600 mg of pentoxifylline per day, in two doses, to three male patients and observed the subsequent changes in clinical symptoms and neutrophil functions. All patients gave informed consent.

Case Reports

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All three patients had eye involvements specific to Behcet disease. We administered pentoxifylline, 600 mg per day, for 2 weeks and then continued pentoxifylline therapy at a total daily dosage of 300 mg. None of the patients had side effects that could be attributed to pentoxifylline.

Patient 1

A 35-year-old man who was positive for HLA-B51 antigen had had oral and genital ulcers for 5 years and low-grade iritis for 2 years. He had a history of venous thrombosis of the left leg. He had been receiving colchicine (500 µg/d) for 3 months for misty vision and poor eyesight (VD 0.1 [0.5] and Vs 0.01 [0.1]). Despite this therapy, he had had recurrent exacerbations of uveitis. The clinical use of pentoxifylline successfully controlled eye involvement, and after 2 weeks of pentoxifylline therapy, visual acuity was recovered to VD 0.7 (1.5) and Vs 0.3 (1.2). The patient has been asymptomatic for 9 months except for an episode of mild epididymitis.

Patient 2

A 32-year-old man who was positive for HLA-B51 antigen received a diagnosis of Behcet disease on the basis of eye involvement (uveitis) and the presence of oral and genital ulcers and idiopathic epididymitis. Prednisolone had been used to treat the ocular attacks (opacity, retinovasculitis, and poor visual acuity [VD 0.1 (0.3) and Vs 0.05 (0.2)]), but clinical improvement did not occur before treatment with pentoxifylline. During the first 2 weeks of pentoxifylline therapy, visual acuity was recovered to VD 0.5 (1.2) and Vs 0.7 (1.2). Nine months later, the patient remained well and had no eye involvement. When pentoxifylline therapy was discontinued for 3 weeks, the patient had a recurrent episode of oral ulcers.

Patient 3

A 17-year-old man who was positive for HLA-B51 antigen had systemic symptoms, had had persistent fever for 3 months (> 38 °C), and had a C-reactive protein concentration of 15.3 mg/dL. He also had mild iridocyclitis, hypopyon, oral ulcers, and folliculitis. Pentoxifylline quickly alleviated the fever Figure 1, and the C-reactive protein concentration had decreased to 2.5 mg/dL 2 weeks after the initiation of pentoxifylline therapy. Other symptoms also rapidly disappeared. The patient remained afebrile and asymptomatic over 7 months of follow-up, and his C-reactive protein concentration was less than 0.5 mg/dL for the last 3 months of that 7-month period.

View larger version (18K): [in this window] [in a new window]   Figure 1. Clinical course of patient 3. Pentoxifylline therapy was started at 600 mg/d on 27 April 1995 and was reduced to 300 mg/d 2 weeks later. This therapy alleviated the patient's oral ulcers and iridocyclitis and decreased his C-reactive protein concentration and body temperature. Other symptoms, including hypopyon and folliculitis, also disappeared with this treatment.

Methods

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We measured neutrophil motility using the agarose plate method [3]. The chemoattractant was n-formylmethionyl-leucyl-phenylalanine (FMLP; 2 x 10^–7 mol/L). Production of O_2– was measured using the method of Cohen and Chovaniec [4]. The release of superoxide was measured as the change in absorbance at 550 nm of cytochrome c. The reaction was done for 2 minutes with FMLP (1 µmol/L).

Neutrophil Functions

Before treatment with pentoxifylline, neutrophil chemotaxis (assembly of microtubules) was increased (120% in patient 1, 118% in patient 2, and 124% in patient 3) compared with a control value. After 2 weeks of pentoxifylline treatment, chemotaxis had returned to normal in all three patients.

Increased (2.5- to 4-fold) levels of O_2– were detected in all patients before administration of pentoxifylline (Figure 2). Neutrophils isolated from the patients during pentoxifylline treatment showed normal levels of O_2– on FMLP stimulation.

View larger version (29K): [in this window] [in a new window]   Figure 2. Effect of pentoxifylline treatment on production of superoxide by neutrophils stimulated with n-formylmethionyl-leucylphenylalanine (1 µmol/L). Before equals before administration of pentoxifylline; during equals 2 weeks after the start of pentoxifylline therapy. Values are the average of measurements obtained on three samples for each patient. The shaded area denotes the mean ±SD of controls (n = 10).

Discussion

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In patients with Behcet disease, neutrophil infiltration can be induced by needle trauma (pathergy); such infiltration is also manifested in uveitis and in ocular attacks. Excessive accumulation of neutrophils may lead to the cutaneous and other lesions seen in patients with this disease. Prolonged or excessive neutrophil activation can initiate a microvascular injury, resulting in increased incidences of hemorrhage and thrombosis [5]. Pentoxifylline changes cell membrane fluidity and modulates membrane-receptor function, leading to decreases in superoxide production by neutrophils [1, 2, 6]. In our patients, pentoxifylline administration reduced production of O_2– by neutrophils and improved clinical symptoms.

Colchicine, which inhibits chemotaxis, has been widely used in Japan to control Behcet disease [7]. This drug does not inhibit the production of superoxide by neutrophils but rather potentiates the release of O_2– [8]. It is not superior to placebo in the treatment of Behcet disease [9] and can no longer be recommended for controlling the eye involvement seen with this condition [10]. Furthermore, colchicine has a critical disadvantage: It can cause infertility in young male patients. Cyclosporine and steroids are effective in controlling Behcet disease [11], but they produce severe side effects. We treated all three of our patients with pentoxifylline; they improved clinically and have had no further ocular attacks in a follow-up period of more than 7 months. Pentoxifylline has no major side effects, with the exception of hypersensitivity. Although we studied only a few patients, we believe that pentoxifylline may be valuable in the treatment of Behcet disease. A randomized, controlled study of this approach should now be done.

Dr. Ohta: Department of Ophthalmology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390, Japan.

Dr. Kobayashi: Second Department of Internal Medicine, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390, Japan.

Dr. Aizawa: Department of Geriatrics, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390, Japan.