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Clinicopathologic Reports, Case Reports, and Small Case Series
February 2005

Therapeutic Neutrophil Apheresis in Patients With Ocular Behçet Disease

Arch Ophthalmol. 2005;123(2):267-269. doi:10.1001/archopht.123.2.267

Behçet disease (BD) is an inflammatory disorder of unknown cause with recurrent ocular, vascular, central nervous system, articular, mucocutaneous, and gastrointestinal manifestations. Most manifestations of BD are self-limiting, but repeated attacks of uveitis are a major cause of blindness.1 Behçet disease is prevalent and is a major cause of morbidity in most Asian nations, countries along the ancient Silk Road, and the Mediterranean basin.1

Biopsy specimens from active lesions of BD show large numbers of neutrophils in the absence of infection, and neutrophils from patients with BD show increased superoxide anion production, enhanced chemotaxis, and excessive release of granular enzymes, indicating neutrophil hyperactivity in BD.1 Similarly, levels of circulating tissue necrosis factor α, interleukin (IL) 1β, and IL-8 are high, and it is believed that these cytokines are involved in neutrophil activation and the enhanced cellular interactions between neutrophils and endothelial cells as a consequences of up-regulated expression of adhesion molecules (Mac-1 and intracellular adhesion molecule 1 [ICAM-1]).1,2 Therefore, we thought that patients with ocular lesions should respond to therapeutic reduction of neutrophils from peripheral blood by selective adsorption apheresis. This treatment in patients with refractory inflammatory bowel disease has produced dramatic and sustained clinical efficacy together with striking reductions in the amounts of tumor necrosis factor α, IL-1β, IL-6, and IL-8 produced by peripheral-blood leukocytes,3 the very cytokines that are thought to be involved in the perpetuation of BD.

Methods

Four male patients (Table) were given 5 sessions of adsorptive neutrophil apheresis, 1 session per week for 5 consecutive weeks, by means of an adsorptive-type extracorporeal leukocyte apheresis device (Adacolumn; Japan Immunoresearch Laboratories Co Ltd, Gunma, Japan) filled with cellulose acetate beads, which adsorb neutrophils, monocytes, and a small population of lymphocytes (Fcγ receptors and complement receptors bearing leukocytes).3 Typically, the column carriers adsorb about 65% of neutrophils, 55% of monocytes, and a small fraction of lymphocytes from the blood in the column. Blood from one antecubital vein perfused the column and returned to the patient via the antecubital vein on the contralateral arm. Duration of 1 session was 60 minutes, at 30 mL/min.

Patient Characteristics and Treatment Outcome
Patient Characteristics and Treatment Outcome

The treatment was given according to a study design in which each patient was closely monitored for 6 months before the present treatment and 6 months after the start of this treatment. During each 6-month period, the numbers of major and minor attacks were recorded (Figure). A major attack was defined as an anterior inflammation associated with hypopyon or posterior inflammation associated with retinal exudates extending to more than 2 quarters of the entire retina. A minor attack was defined as a posterior ocular episode of inflammation in 2 quarters of the retina or less, or anterior inflammation without hypopyon. Patients were selected according to the following 4 criteria: (1) a confirmed diagnosis of BD; (2) presence of ocular BD; (3) frequent ocular attacks; and (4) lack of response to high-dose immunosuppressants, or withdrawal of the medication because of severe side effects. Our study design and the treatment outcomes for all 4 cases are presented in the Figure. All patients were receiving colchicine, 0.5 to 1 mg/d, and prednisolone acetate, 5 to 10 mg/d (Table). These medications were continued during the 6 months before and after adsorptive neutrophil apheresis therapy. The study protocol was approved by our institutional ethics committee, and all patients provided informed consent before the initiation of this therapy.

Figure.
Study design and symptom monitoring for 4 patients with ocular Behçet disease who received adsorptive neutrophil apheresis therapy. Solid and open arrows represent major and minor attacks, respectively, during the 6 months before the start of the new therapy and then for a second 6 months from the start of this therapy.

Study design and symptom monitoring for 4 patients with ocular Behçet disease who received adsorptive neutrophil apheresis therapy. Solid and open arrows represent major and minor attacks, respectively, during the 6 months before the start of the new therapy and then for a second 6 months from the start of this therapy.

Results

Patients had mild leukocytosis; the mean±SD leukocyte count just before this therapy was 10 800 ± 3400 cells/μL, and 89% ± 2% was neutrophils. At 6 months after therapy, the leukocyte count was reduced to 7900 ± 2800 cells/μL, with 67% ± 8% neutrophils. The total number of ocular BD attacks during the 6 months after neutrophil adsorption therapy was decreased in all 4 patients (Figure). The mean±SD number of attacks was 2.5 ± 0.6 compared with 5.0 ± 1.8 (P = .04) during the preceding 6 months, and 3 of 4 patients were free of major attacks. We evaluated the efficacy of this new treatment by monitoring the frequency of ocular attacks rather than measuring changes in visual acuity. This is because many patients with BD have irreversible retinal damage and, therefore, not much can be done to dramatically improve their visual acuity. For these cases, the reduction in frequency of ocular attacks and the prevention of major attacks improved the quality of vision. Nonetheless, the treatment improved visual acuity in all 4 patients (Table). Although this study was not designed to monitor the effect of this therapy on the nonocular manifestations of BD, patients with diarrhea reported cessation of this symptom, and 2 patients with aphthous ulcers had improvement of the ulcers during the treatment. No adverse effects were observed either during the therapy or in the follow-up period.

Comment

Ocular BD is a debilitating condition that affects people throughout the world and responds poorly to drug therapy. Drugs that are frequently given to patients with ocular BD include colchicine, corticosteroids, azathioprine, chlorambucil, cyclophosphamide, and cyclosporine. All of these agents can cause adverse effects, causing the patients to suffer disease symptoms as well as drug toxic effects. In contrast, this new treatment produced no adverse effects in this small study and appeared to be an effective adjunct to conventional therapy for BD. Furthermore, although not specifically investigated, most patients reported feeling better after each neutrophil adsorption session. This is similar to the experience reported during treatment of patients with ulcerative colitis.3

Neutrophil hyperactivity and elevated inflammatory cytokine levels are hallmarks of ocular BD. Neutrophils and monocytes produce inflammatory cytokines, which promote neutrophil activity. This creates a vicious cycle in which elevated and activated neutrophils produce more cytokines and the latter enhance neutrophil activity. When activated neutrophils are eliminated, the prevailing cytokine field may be extinguished. The net effect should be remission of disease. Accordingly, reduction of neutrophils seemed to reduce ocular attacks in our 4 cases. However, evaluation of the full efficacy of this therapy for BD requires more adsorption sessions and determination of the most appropriate frequency of therapy. Furthermore, this procedure does not extensively deplete T cells, which are thought to have a significant role in the posterior ocular attacks.4

In the present study, we did not monitor cytokine profiles, but a study in patients with ulcerative colitis reported a marked reduction in the ability of blood leukocytes to produce inflammatory cytokines.3 More recently published data5 show that neutrophils and monocytes, when adsorbed to the column’s cellulose acetate carriers, release large amounts of IL-1 receptor antagonist, which has strong anti-inflammatory effects and is taken to the patients by the returning blood during apheresis therapy.

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Article Information

Correspondence: Dr Sonoda, Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan (sonodak@med.kyushu-u.ac.jp).

Funding/Support: This work was supported by grant B2 No. 14770962 from the Ministry of Education, Science, Sports and Culture of Japan and a grant from the Japan National Society for the Prevention of Blindness.

References
1.
Sakane  TTakeno  MSuzuki  NInaba  G Behçet’s disease. N Engl J Med 1999;3411284- 1291
PubMedArticle
2.
Ehrlich  GE Vaculitis in Behcet’s disease. Int Rev Immunol 1997;1481- 88
PubMedArticle
3.
Hanai  HWatanabe  FSaniabadi  AMatsushita  ITakeuchi  KIida  T Therapeutic efficacy of granulocyte and monocyte adsorption apheresis in severe active ulcerative colitis. Dig Dis Sci 2002;472349- 2353
PubMedArticle
4.
Foster  CSFaris  BM Adamantiades-Behçet disease. Albert DMJakobiec FAeds.Principles and Practice of Ophthalmology. Philadelphia, Pa WB Saunders2000;2216- 2217
5.
Takeda  YHiraishi  KTakeda  H  et al.  Cellulose acetate beads induce release of interleukin-1 receptor antagonist, but not tumour necrosis factor-alpha or interleukin-1beta in human peripheral blood. Inflamm Res 2003;52287- 290
PubMed
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