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Filtering out the Phagocytes in Inflammatory Bowel Disease

Brown, Steven J MD; Ullman, Thomas MD; Sachar, David B MD

Journal of Clinical Gastroenterology: November-December 2005 - Volume 39 - Issue 10 - p 845-846
doi: 10.1097/01.mcg.0000180807.58737.e7
Editorial
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From the Henry Janowitz Division of Gastroenterology, Mount Sinai Hospital, New York, NY.

Reprints: Steven J. Brown, MD, The Department of Medicine, The University of Melbourne, St. Vincent's Hospital, 41 Victoria Parade Fitzroy, VIC 3065 Australia (e-mail: steven.brown@svhm.org.au).

Leukocytapheresis is a modern-day variation of an ancient medicinal technique, bloodletting. But by selectively filtering out monocytes and neutrophils, and then returning the rest of the blood to the patient, leukocytapheresis seeks to reverse Shaw's doctor's advice (“Stimulate the phagocytes”) and to implement Shakespeare's King Richard's (“Let's purge this choler without letting blood”).

As a therapy for inflammatory bowel disease, leukocytapheresis was proposed almost 20 years ago,1 although it has not been uniformly embraced. Japanese investigators, however, have increasingly used leukocytapheresis, particularly in ulcerative colitis (UC). Despite its common use in Japan, the effectiveness of leukocytapheresis in UC has yet to be clearly established by adequately controlled studies. Nonetheless, there are tantalizing suggestions that leukocytapheresis may provide an alternative, potentially drug-free method for inducing remission in moderate to severe UC.

Ctyapharesis is used to treat a number of immune-mediated diseases, often with well-defined and dramatic responses, and there is a clear rationale for its use in active UC. Whatever the primary pathogenic mechanism may be in UC, systemic immune activation is a hallmark. Peripheral blood neutrophils are commonly increased, and mucosal damage is largely mediated by the influx of inflammatory cells to the intestine. Depleting the peripheral pool of these cells should limit their availability to be recruited and thus should inhibit inflammation. Leukocytapheresis therapy reduces systemic monocyte and neutrophil counts,2 and this is associated with clinical response. Besides being decreased in number, the peripheral blood mononuclear cells that persist after leukocytapheresis therapy exhibit a number of altered properties,3-5 suggesting that leukocytapheresis does more than simply minimize the available pool of inflammatory cells. It remains unknown, however, whether activated immune cells within the gut can actually be “leached out” via leukocytapheresis therapy. It is also unclear whether depleting peripheral immune cells offers any benefit in the maintenance of remission, which might require specific targeting of the mucosal immune system. There are three major types of leukocytapheresis technologies that have been examined in UC. Traditional leukocytapheresis involves passage of peripheral blood through a leukocyte removal filter and then reinfusion back into the patient. This methodology includes the Cellsorba system (Asahi Kasei Medical, Tokyo, Japan), which is currently being evaluated in small pilot studies in the United States. It typically removes 99% of both granulocytes and monocytes and about 70% of lymphocytes.6 In contrast, the Adacolumn system (Japan Immunoresearch Laboratories (JIMRO), Gunma, Japan) provides selective depletion of granulocytes and monocytes via passage through cellulose acetate beads that adhere to the cells' Fcg and complement receptors. Third, the centrifugal system uses a single-vein access and centrifugal force to intermittently spin down blood into a nonselective “buffy” coat, which is removed prior to reinfusion.7 A further variation of leukocytapheresis, known as extracorporeal phototherapy, involves ex vivo phototherapy to maximize the removal of sensitized leukocytes.

Despite the differences in leukocytapheresis technologies, published reports indicate similar effects in UC, and they are often considered collectively. Indeed, the Honmas study in this issue of the Journal groups both Cellsorba and centrifugal leukocytapheresis subjects together for most analyses, as have previous studies.8 It is therefore impossible to determine whether one particular technique offers a therapeutic advantage over another. It also remains difficult to comment as to whether leukocytapheresis in general offers a distinct advantage over the currently available therapies for UC, given the absence of controlled comparative studies. Nonetheless, impressive clinical responses are increasingly being reported with leukocytapheresis.

Leukocytapheresis appears to benefit both steroid-naive and steroid-resistant UC. An uncontrolled study2 examined 20 steroid-naive subjects, not responding to at least 8 weeks of mesalamine-based agents, treated with Adacolumn leukocytapheresis twice a week for 3 to 5 weeks. The mean clinical activity index fell from 8.6 to 3.0 and remission was achieved in 85%. Significant endoscopic and C-reactive protein responses were also documented. Whereas uncontrolled, the 85% remission rate is impressive, and well in excess of those seen in most placebo-treated subjects. Similar efficacy was recently reported in a landmark study9 involving subjects not responding to 2 weeks of steroid therapy. Importantly, this study of Cellsorba leukocytapheresis also included a “sham” leukocytapheresis arm, to control for the confounding effects of extracorporeal circulation and anti-coagulation. Leukocytapheresis also appears to benefit steroid-dependent10 and steroid-refractory UC, although many studies are hampered by ill-defined endpoints, unspecified concomitant medications, and variable leukocytapheresis regimens. Despite such criticisms, response rates ranging from 60% to 90% are common.7,11-13

The ability of leukocytapharesis to maintain remission in UC has not previously been addressed. The possibility that induction leukocytapheresis may result in long-lasting remission has been suggested by several studies,2,11 although the use of concomitant medications has not been clearly defined. In contrast, a small study of 7 steroid-resistant or -dependent patients receiving maintenance leukocytapheresis (1-2×/month) reported 12-month steroid-free remission in only 4 (57%).8 The article by Honma et al in this issue of the Journal greatly expands our knowledge of this approach to therapy for UC. Their report, however, leaves behind some of the same questions it attempts to answer. Is leukocytapheresis effective at inducing remission as their title declares? Is it truly ineffective at maintaining remissions?

In this study, a combination of filtration and centrifugation techniques was associated with remission at 5 weeks in 23 of 25 patients with moderate to severe steroid-resistant UC. In addition to the lack of a control arm, the nature of remission assessment is inadequately defined in the study's methods: the timing and performance of the outcome assessment are not specified; and whether the person assessing the patient (also unknown) was blinded to the therapy and hypothesis (not given a priori) was not stated. Although none of these features alone would greatly damage a study of this kind, their combined effect is profoundly troubling.

Likewise, the maintenance period of this study is also difficult to interpret. Aside from tapering of corticosteroids and keeping mesalamine and sulfasalazine doses constant during follow-up, no mention is made of the use of immunomodulators or other medications during the maintenance period. Similar to the problems in calculating remissions, the timing of assessment for relapse and the performance of such assessment are vague. (Curiously, the authors use the Lichtiger score for assessment of relapse when Truelove and Witts criteria were used for entry.) We might also ask why only 12 patients were available for assessment in the “conventional” group.

Whatever the assessment technique may have been, though, the relapse rate of 50% at 1 year in the treated subjects seems high. It seems, therefore, that 4-weekly leukocytapheresis is inadequate to maintain remission. Whether more frequent treatment or the concomitant use of immunomodulatory therapy might result in prolonged remissions remains unknown.

Further trials that directly compare this promising, and seemingly safe, treatment to either placebo or a known active agent are still needed to establish its role in inducing remission in moderate to severe steroid-resistant UC. By the same token, a more rigorous controlled trial of leukocytapheresis administered at more frequent intervals could tell us more about the potential benefits of this therapy for maintenance of remission. Meanwhile, Honma et al have done us a great service by enlarging our experience of this innovative therapeutic approach and by providing an updated version of Shaw's century-old advice: “Filter out the phagocytes.”

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© 2005 Lippincott Williams & Wilkins, Inc.