- Citado por SciELO
versión impresa ISSN 1130-0108
Rev. esp. enferm. dig. v.96 n.7 Madrid jul. 2004
Experience with granulocytapheresis in Crohn's disease
F. Cuenca, J. García-Paredes, J. L. Mendoza, D. M. Cruz, A. Herrero1 and M. Díaz-Rubio
Service of Digestive Diseases. IBD Unit. 1Service of Nephrology. Hospital Clínico San Carlos. Madrid, Spain
Objective: to describe our experience with granulocyte apheresis to induce remission in patients with active Crohn's disease refractory to conventional treatment. We summarize the results previously obtained with this technique.
Conclusions: granulocyte apheresis is a safe and well tolerated therapeutic modality that can be a valid therapeutic alternative in the induction of remission in inflammatory bowel disease, although controlled clinical trials must be conducted to define long-term efficacy, as well as to establish “optimal patient” selection, re-treatment interval, and number of sessions.
Key words: Granulocyte apheresis. Leukocyte apheresis. Ulcerative colitis. Crohn's disease. Inflammatory bowel disease.
Cuenca F, García-Paredes J, Mendoza JL, Cruz DM, Herrero A, Díaz-Rubio M. Experience with granulocytapheresis in Crohn's disease. Rev Esp Enferm Dig 2004; 96: 501-506.
Correspondencia: Francisca Cuenca Alarcón. Servicio de Aparato Digestivo.-Unidad EII. Hospital Clínico San Carlos. C/ Martín Lagos, s/n. 28040 Madrid.
Crohn's disease (CD) and ulcerative colitis (UC) are chronic gastrointestinal diseases of unknown etiology that are included within the concept of inflammatory bowel disease (IBD). Like other autoimmune diseases, IBD is frequently associated with increased neutrophils and leukocyte-derived proinflammatory soluble factors in peripheral blood.
In the active forms of IBD there is extravasation of an important number of neutrophils and monocytes/macrophages into the mucous tissue. The infiltrating leukocytes may cause extensive damage to the mucosa of the gastrointestinal tract through the release of degradation proteases, oxidation radicals and proinflammatory cytokines.
A large part of the watery diarrhea that occurs in active IBD is a consequence of decreased water reabsorption by the damaged cells of the absorptive epithelium. The apparent association between infiltration of neutrophils and monocytes/macrophages and lesion of the intestinal mucosa has led to the use of measures targeting the reduction of the inflammatory reaction in the active forms of IBD through, amongst others, the selective extraction of activated leukocytes and proinflammatory cytokines.
There are three different types of cytapheresis techniques: lymphocytapheresis, which, by means of centrifugation techniques, extracts lymphocytes and granulocytes; granulocytapheresis (GCAP), which extracts granulocytes and monocytes by cellulose diacetate filtering, and leukocytapheresis, which uses a Cellsorba filter and extracts granulocytes, monocytes and lymphocytes.
Cytapharesis was originally used in other autoimmune conditions such as rheumatoid arthritis; experience in this field gave rise to its application in IBD. The first experiences with lymphocytapheresis were published, in 1989, by Bicks et al. in Memphis, USA (1) and, in 1988, by the group of Faradji A et al., in France (2), in 7 and 12 patients with active CD, respectively, with encouraging results, since remission rates of 50% were achieved. In the last ten years, most of the studies published have been conducted in Japan (3-8), with good results obtained above all in UC.
DESCRIPTION OF GRANULOCYTAPHERESIS TECHNIQUES
It is an extracorporeal treatment that consists of running blood through a 335-ml cartridge containing 220 g of cellulose diacetate in the form of 2-mm-diameter beads (around 35,000), washed in isotonic saline solution (Adacolumn®, Otsuka). Blood circulates at a rate of 30 ml/min. Output and return from/to the circuit takes place preferably through the veins in both arms although, when not possible, a central catheter will be used. Hitherto, sessions lasting 60 minutes have been conducted on a weekly basis for 5 to 10 consecutive weeks, depending on the center.
Three patients with active corticosteroid-dependent or corticosteroid-resistant Crohn's disease with moderate activity in whom conventional treatment had not been effective (aminosalicylates, azathioprine/6-MP, methotrexate and infliximab) were included. GCAP sessions were conducted for five consecutive weeks with a subsequent monthly follow-up until the sixth month. The activity index (CDAI, Crohn's Disease Activity Index), corticosteroid dose reduction, maintenance of remission, safety and tolerance of treatment, and quality of life were all measured.
First case. A woman aged 36 years was diagnosed with the disease following acute abdomen surgery, and underwent resection for ileocecal and sigma region involvement, with termino-terminal anastomosis 16 years before, with subsequent fistulizing evolution and on treatment with TPMT (tiopuril-methyl-transfer)-adjusted azathioprine for 3 years, despite which she required corticosteroids on several occasions for bouts of activity. Re-operated in the previous 6 months for intraabdominal abscess and relapses in the anastomotic mouth.
Treatment started following a bout of activity scoring 252 points on CDAI, with progressive clinical improvement as of the second session. Scoring at end of treatment was 203, and remission was achieved after 2 months, having been maintained for one year post-treatment thereafter.
Second case. A woman aged 49 years was diagnosed with the disease five years previously, and underwent surgery for ileocolonic involvement and the development of an intraabdominal abscess, with ileocecal resection, colonic exclusion and discharge ileostomy. On treatment with oral corticosteroids at a dose of 16 mg of methylprednisolone daily (as only treatment for intolerance to immunosuppressants, following development of aplastic anemia secondary to methotrexate and lack of response to infliximab). As an iatrogenic complication, she developed a pathological fracture of L5 due to generalized osteoporosis. Following a bout of activity with a CDAI of 262, treatment was initiated with GCAP with a fall of 92 points in CDAI after 5 weeks with corticosteroids reduced to a half, but with a worsening two months after onset, with surgical treatment being indicated.
Third case. A woman aged 31 years was diagnosed with Crohn's disease at the age of 23, with fistulizing perianal disease and colonic involvement; on treatment with TPMT-adjusted azathioprine, refractory to corticosteroids (at a dose of 1 mg/kg weight) and lack of response to infliximab. Treatment with GCAP led to a fall in CDAI from 307 to 157 one week after completion, thus permitting a progressive reduction of corticosteroid doses. A reactivation of the disease occurred after three months of treatment.
In quality of life measurements, these three patients presented a significant improvement during treatment, which was maintained after two months in the first and third case.
No complications were observed during treatment, which was well tolerated in the three cases, with no adverse effects in the subsequent follow-up. In the first two patients it proved necessary to implant a central catheter throughout the five weeks of treatment, although this operation presented no associated complications.
IBD is a chronic condition for which no single etiological agent has been identified. It is thought that environmental factors impact generically susceptible hosts, and would give rise to an altered immunological response to bacterial antigens of the normal intestinal flora. Its treatment is still a challenge and depends on the localization and extension of affected areas, as well as on severity. Current drug treatment includes the use of antiinflammatory drugs (aminosalicylates and corticosteroids), immunomodulators (azathioprine, 6-mercaptopurine, cyclosporine, methotrexate and biological agents), and antibiotics, a therapeutic armamentarium which does not manage to heal the process, and which in some cases has undesirable adverse effects.
As mentioned at the beginning, the use of cytapheresis techniques actually began for other autoimmune diseases such as rheumatoid arthritis at the end of the 1970s, as a coadjuvant of conventional treatment (9). The first works on the application of this treatment in IBD were developed one decade later in short series of patients with CD.
Most studies published in recent years -the majority being Japanese- are uncontrolled clinical trials. They have been applied to patients with UC (most frequently) and with CD in an attempt to cater for those who are refractory to conventional treatment, and in whom the continuous administration of corticosteroids causes major side effects. The results obtained show overall remission rates ranging from 62 to 100% (3-8,10-13). Shimoyama T et al. (14) conducted a randomized controlled clinical trial into which they enrolled 105 patients with active UC; 52 patients were treated with 5 sessions of GCAP and 53 with prednisolone, with a global response rate of 58 vs 44%, 74 vs 65%, and 56 vs 38% after 6 weeks, 12 and 24 months, respectively. Recently, another controlled trial performed by Sawada et al. (15) in patients with UC compared treatment with leukocytapheresis plus corticosteroids in 39 patients vs 37 treated only with high doses of corticosteroids. Fewer adverse effects and a greater response rate (74 vs 38%) were observed in the leukocytapheresis plus corticosteroids group.
These works neither address the different clinical patterns of the disease, nor clearly define the situation of corticosteroid resistance/corticosteroid dependence.
To summarize, cytapheresis in IBD has been applied as an attempt to “spare corticosteroids” and thus avoid their harmful effects.
Adverse reactions to cytapheresis, probably due to a low blood flow (30 ml/min), have been uncommon, generally speaking. Nagase K et al. (16) reported 9.9% out of a total of 1978 sessions. Most frequent adverse events include: dizziness, palpitations, hypotension, malaise, headache, nausea, vomiting, fever and difficulty in accessing the vein. Overall, these disorders were mild and easy to handle, and did not render it necessary that treatment be discontinued.
The term of GCAP is due to initial observations made following its application in patients with rheumatoid arthritis and IBD, in whom a reduction in neutrophils and monocytes was observed in the blood coming out of the cartridge versus incoming blood. Nevertheless, subsequent works have shown that there is not a significant variation in the figure of peripheral blood neutrophils and monocytes after a session (17,18). However, a reduction in the count of neutrophils has been described in peripheral blood 30 minutes after onset, from 4,520 ± 690 mm3 to 2,420 ± 490 mm3 (p < 0.01), with a rapid subsequent increase, so that after 60 minutes they did not differ significantly from baseline values.
The contact of blood with cellulose diacetate beads induces a change in the expression of adhesion molecules, with a marked increase in the expression of integrins, CD11b-18 (Mac-1), and a decreased expression of L-selectin (12), as well as a reduction in the release of cytokines such as TNF-α, interleukin-1ß, interleukin-6 and interleukin-8 following incubation with lipopolysaccharide (LPS), thus giving rise to a reduction in the chemotactic response of neutrophils and their adhesion capacity and finally an increase in the apoptosis of neutrophils and monocytes (14,18,20).
The study of Muratov (17) describes, in patients treated with GCAP, a reduction in CD4+INFγ cells, a key factor in the immune-regulating events of mucous inflammation. Furthermore, Tsukada et al. (19) observed, following the treatment of 7 patients, that patients with higher levels of IL-8 (5 patients) responded best to treatment with GCAP, proposing it as a response factor to treatment.
Although the mechanisms of the possible therapeutic effect of GCAP have not been well established, its action is not believed to be due to the small fraction of neutrophils/monocytes adsorbed by the cellulose diacetate beads, but rather to a cell immunomodulatory action generated by their contact with the cellulose.
We present the clinical evolution of three difficult patients with Crohn's disease who failed to respond to conventional treatment and who were treated with granulocyte apheresis plus corticosteroids. As has already been published, granulocyte apheresis is a safe and well tolerated treatment, and may be a therapeutic option in the induction of remission, reducing the need for high doses of corticosteroids. A greater number of controlled clinical trials will be required to define the efficacy of the technique, "optimal patient" selection, total number of sessions, and re-treatment interval.
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