Therapeutic Neutrophil Apheresis in Patients with Ocular Behçet Disease

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

spond to therapeutic reduction of patient was closely monitored for 6 Therapeutic Neutrophil neutrophils from peripheral blood by months before the present treat- Apheresis in Patients selective adsorption apheresis. This ment and 6 months after the start of With Ocular Behçet Disease treatment in patients with refrac- this treatment. During each 6-month tory inflammatory bowel disease has period, the numbers of major and mi- Behçet disease (BD) is an inflamma- produced dramatic and sustained nor attacks were recorded (Figure). tory disorder of unknown cause with clinical efficacy together with strik- A major attack was defined as an an- recurrent ocular, vascular, central ing reductions in the amounts of tu- terior inflammation associated with nervous system, articular, mucocu- mor necrosis factor ␣, IL-1␤, IL-6, hypopyon or posterior inflamma- taneous, and gastrointestinal mani- and IL-8 produced by peripheral- tion associated with retinal exu- festations. Most manifestations of BD blood leukocytes,3 the very cyto- dates extending to more than 2 quar- are self-limiting, but repeated at- kines that are thought to be in- ters of the entire retina. A minor tacks of uveitis are a major cause of volved in the perpetuation of BD. attack was defined as a posterior ocu- blindness.1 Behçet disease is preva- lar episode of inflammation in 2 quar- lent and is a major cause of morbid- Methods. Four male patients ters of the retina or less, or anterior ity in most Asian nations, coun- (Table) were given 5 sessions of ad- inflammation without hypopyon. Pa- tries along the ancient Silk Road, and sorptive neutrophil apheresis, 1 ses- tients were selected according to the the Mediterranean basin.1 sion per week for 5 consecutive following 4 criteria: (1) a confirmed Biopsy specimens from active le- weeks, by means of an adsorptive- diagnosis of BD; (2) presence of ocu- sions of BD show large numbers of type extracorporeal leukocyte apher- lar BD; (3) frequent ocular attacks; neutrophils in the absence of infec- esis device (Adacolumn; Japan Im- and (4) lack of response to high- tion, and neutrophils from patients munoresearch Laboratories Co Ltd, dose immunosuppressants, or with- with BD show increased superox- Gunma, Japan) filled with cellu- drawal of the medication because of ide anion production, enhanced che- lose acetate beads, which adsorb severe side effects. Our study design motaxis, and excessive release of neutrophils, monocytes, and a small and the treatment outcomes for all 4 granular enzymes, indicating neu- population of lymphocytes (Fc␥ re- cases are presented in the Figure. All trophil hyperactivity in BD.1 Simi- ceptors and complement receptors patients were receiving colchicine, 0.5 larly, levels of circulating tissue ne- bearing leukocytes).3 Typically, the to 1 mg/d, and prednisolone ac- crosis factor ␣, interleukin (IL) 1␤, column carriers adsorb about 65% etate, 5 to 10 mg/d (Table). These and IL-8 are high, and it is believed of neutrophils, 55% of monocytes, medications were continued during that these cytokines are involved in and a small fraction of lympho- the 6 months before and after ad- neutrophil activation and the en- cytes from the blood in the col- sorptive neutrophil apheresis therapy. hanced cellular interactions be- umn. Blood from one antecubital The study protocol was approved by tween neutrophils and endothelial vein perfused the column and re- our institutional ethics committee, cells as a consequences of up- turned to the patient via the ante- and all patients provided informed regulated expression of adhesion cubital vein on the contralateral arm. consent before the initiation of this molecules (Mac-1 and intracellular Duration of 1 session was 60 min- therapy. adhesion molecule 1 [ICAM-1]).1,2 utes, at 30 mL/min. Therefore, we thought that pa- The treatment was given accord- Results. Patients had mild leukocy- tients with ocular lesions should re- ing to a study design in which each tosis; the mean±SD leukocyte count

Patient Characteristics and Treatment Outcome

Visual Acuity

Before New Therapy 6 mo After New Therapy Patient No./ Duration Concomitant Sex/Age, y of BD, y Medication* OD OS OD OS 1/M/32 13 Colchicine, prednisolone HM 3/100 HM 9/100 2/M/25 5 Colchicine, prednisolone Null HM Null 1/100 3/M/20 3 Colchicine, prednisolone 20/60 20/30 20/60 20/25 4/M/46 14 Colchicine, prednisolone 20/100 CF 20/50 CF

Abbreviations: BD, Behçet disease; CF, counting fingers; HM, hand motions. *The dosage of prednisolone acetate was 5 to 10 mg/d per patient, while the dosage of colchicine was 0.5 to 1.0 mg/d per patient.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 ates a vicious cycle in which el- Case 1 evated and activated neutrophils 2001 2002 Sept Oct Nov Dec Jan Feb March April May June July Aug Sept Oct Nov produce more cytokines and the lat- ter enhance neutrophil activity. Neutrophil When activated neutrophils are Apheresis eliminated, the prevailing cytokine Case 2 field may be extinguished. The net 2001 2002 effect should be remission of dis- Sept Oct Nov Dec Jan Feb March April May June July Aug Sept Oct Nov ease. Accordingly, reduction of neutrophils seemed to reduce ocular at- Neutrophil Apheresis tacks in our 4 cases. However, evaluation of the full efficacy of this Case 3 therapy for BD requires more ad- 2001 2002 sorption sessions and determina- Sept Oct Nov Dec Jan Feb March April May June July Aug Sept Oct Nov tion of the most appropriate fre- Neutrophil quency of therapy. Furthermore, this Apheresis procedure does not extensively de- Case 4 plete T cells, which are thought to 2001 2002 have a significant role in the poste- 4 Sept Oct Nov Dec Jan Feb March April May June July Aug Sept Oct Nov rior ocular attacks. In the present study, we did not Neutrophil monitor cytokine profiles, but a Apheresis study in patients with ulcerative co- Figure. Study design and symptom monitoring for 4 patients with ocular Behçet disease who received litis reported a marked reduction in adsorptive neutrophil apheresis therapy. Solid and open arrows represent major and minor attacks, the ability of blood leukocytes to respectively, during the 6 months before the start of the new therapy and then for a second 6 months produce inflammatory cytokines.3 from the start of this therapy. More recently published data5 show that neutrophils and monocytes, just before this therapy was 10 aphthous ulcers had improvement when adsorbed to the column’s cel- 800±3400 cells/µL, and 89%±2% of the ulcers during the treatment. lulose acetate carriers, release large was neutrophils. At 6 months after No adverse effects were observed amounts of IL-1 receptor antago- therapy, the leukocyte count was re- either during the therapy or in the nist, which has strong anti-inflam- duced to 7900±2800 cells/µL, with follow-up period. matory effects and is taken to the pa- 67%±8% neutrophils. The total tients by the returning blood during number of ocular BD attacks dur- Comment. Ocular BD is a debilitat- apheresis therapy. ing the 6 months after neutrophil ad- ing condition that affects people sorption therapy was decreased in all throughout the world and responds Koh-Hei Sonoda, MD, PhD 4 patients (Figure). The mean±SD poorly to drug therapy. Drugs that are Shoich Inaba, MD, PhD number of attacks was 2.5±0.6 com- frequently given to patients with Akiko Ariyama, MD pared with 5.0±1.8 (P=.04) during ocular BD include colchicine, corti- Yoh-Ich Kawano, MD, PhD the preceding 6 months, and 3 of 4 costeroids, azathioprine, chlorambu- Abby Saniabadi, PhD patients were free of major attacks. cil, cyclophosphamide, and cyclo- Tatsuro Ishibashi, MD, PhD We evaluated the efficacy of this new sporine. All of these agents can cause Correspondence: Dr Sonoda, De- treatment by monitoring the fre- adverse effects, causing the patients partment of Ophthalmology, Gradu- quency of ocular attacks rather than to suffer disease symptoms as well as ate School of Medical Sciences, Ky- measuring changes in visual acu- drugtoxiceffects.Incontrast,thisnew ushu University, 3-1-1 Maidashi, ity. This is because many patients treatmentproducednoadverseeffects Higashi-Ku, Fukuoka 812-8582, Ja- with BD have irreversible retinal in this small study and appeared to pan ([email protected] damage and, therefore, not much can beaneffectiveadjuncttoconventional .jp). be done to dramatically improve therapy for BD. Furthermore, al- Funding/Support: This work was their visual acuity. For these cases, though not specifically investigated, supported by grant B2 No. 14770962 the reduction in frequency of ocu- most patients reported feeling better from the Ministry of Education, Sci- lar attacks and the prevention of ma- after each neutrophil adsorption ses- ence, Sports and Culture of Japan jor attacks improved the quality of sion. This is similar to the experience and a grant from the Japan Na- vision. Nonetheless, the treatment reported during treatment of patients tional Society for the Prevention of improved visual acuity in all 4 pa- with ulcerative colitis.3 Blindness. tients (Table). Although this study Neutrophil hyperactivity and el- was not designed to monitor the evated inflammatory cytokine lev- 1. Sakane T, Takeno M, Suzuki N, Inaba G. Be- hçet’s disease. N Engl J Med. 1999;341:1284- effect of this therapy on the nonocu- els are hallmarks of ocular BD. Neu- 1291. lar manifestations of BD, patients trophils and monocytes produce 2. Ehrlich GE. Vaculitis in Behcet’s disease. Int Rev Immunol. 1997;14:81-88. with diarrhea reported cessation of inflammatory cytokines, which pro- 3. Hanai H, Watanabe F, Saniabadi A, Matsushita this symptom, and 2 patients with mote neutrophil activity. This cre- I, Takeuchi K, Iida T. Therapeutic efficacy of

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 granulocyte and monocyte adsorption apher- was removed from the right cornea sition in both eyes. Centrally the cor- esis in severe active ulcerative colitis. Dig Dis Sci. 2002;47:2349-2353. to reduce the central corneal haze. nea was clear in both eyes 4. Foster CS, Faris BM. Adamantiades-Behçet The patient was initially seen in (Figure 1). Corneal topography of disease. In: Albert DM, Jakobiec FA, eds. Prin- ciples and Practice of Ophthalmology. Philadel- June 2002 for a laser-assisted in situ the left eye showed a circular mid- phia, Pa: WB Saunders; 2000:2216-2217. keratomileusis (LASIK) consult. At peripheral steepening from the len- 5. Takeda Y, Hiraishi K, Takeda H, et al. Cellulose that time, the patient’s uncorrected ticle still present within the cornea acetate beads induce release of interleukin-1 receptor antagonist, but not tumour necrosis factor- vision was counting fingers OU. (Figure 2). alpha or interleukin-1beta in human periph- Best-corrected vision in the right eye After much counseling, the pa- eral blood. Inflamm Res. 2003;52:287-290. was 20/20−1 with a dry refraction tient decided to proceed. On July 11, of –7.25−2.50ϫ180 and 20/20 with 2002, LASIK was performed on the a cycloplegic refraction of left eye. The VISX Star 3 excimer la- ϫ Myopic Laser-Assisted −7.00−1.00 180; in the left eye, it ser (VISX Inc, Santa Clara, Calif) and was 20/30+2 with a dry refraction Hansatome microkeratome (Bausch In Situ Keratomileusis ϫ Following Epikeratophakia of −8.50−2. 00 165 and 20/30+2 & Lomb, Rochester, NY) were used. with a cycloplegic refraction of After the flap had been made and ϫ A 48-year-old healthy white man un- −8.00−2.00 165. Pachymetry was lifted in the left eye, a raised ridge derwent bilateral epikeratophakia in 527 µm OD and 672 µm OS. Kera- of corneal tissue was visible in the 1986 for high myopia. After several tometry was 42.50 diopters (D) at 15 midperiphery of the stromal bed. months, his refraction regressed degrees, 44.00 D at 105 degrees OD This midperipheral thickening and slightly and his right cornea devel- and 43.75 D at 10 degrees, 45.50 D elevated corneal tissue was pre- oped central haze. He then had pho- at 100 degrees OS. Anterior and pos- sumed to be the previously placed torefractive keratectomy in both eyes terior segment examination results lenticle. The left eye was treated for for myopia and phototherapeutic were normal except for corneal neo- −7.3−2.00ϫ165. One day postop- keratectomy in the right eye to re- vascularization superiorly and infe- eratively, uncorrected vision was duce the corneal haze, which was not riorly in both eyes and midperiph- 20/100 OS. The flap was in good po- successful. Therefore, in March of eral anterior stromal scarring from sition and clear except for the pre- 1999, the epikeratophakia lenticle the 2-o’clock to the 10-o’clock po- existing stromal scarring. One week

Figure 1. External photographs of the right eye (left) and the left eye (right) showing corneal neovascularization and midperipheral stromal scarring.

Figure 2. Corneal topographies of both eyes after epikeratophakia (the lenticle has been removed from the right eye) and prior to laser-assisted in situ keratomileusis.

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