**Laparoscopic Surgery for Severe Ulcerative Colitis**

Kazuhiro Watanabe, Hitoshi Ogawa, Chikashi Shibata, Koh Miura, Takeshi Naitoh, Masayuki Kakyou, Takanori Morikawa, Sho Haneda, Naoki Tanaka, Katsuyoshi Kudo, Shinobu Ohnuma, Hiyroyuki Sasaki and Iwao Sasaki *Department of Surgery, Tohoku University Graduate School of Medicine Japan* 

#### **1. Introduction**

14 Ulcerative Colitis – Treatments, Special Populations and the Future

Sagar, P.M.; Lewis, W.; Holdsworth, P.J.; Johnston, D.; Mitchell, C. & MacFie, J. (1993)

Selvaggi, F.; Giuliani, A.; Gallo, C.; Signoriello, G.; Riegler, G. & Canonico, S. (2000)

for ulcerative colitis in the maturation period. *Dis Colon Rectum* 43:615-620 Selvaggi, F.; Giuliani, A. & Sciaudone, G (2002) Le disfunzioni delle pouch ileali. *Archivio ed* 

Selvaggi, F.; Sciaudone, G.; Guadagni, I. & Pellino, G. (2010a) Ileal pouch-anal anastomosis

Selvaggi, F.; Sciaudone, G.; Limongelli, P.; Di Stazio, C.; Guadagni, I.; Pellino, G.; De Rosa,

Selvaggi, F.; Silvestri, A.; Scotto Di Carlo, E. & Sciaudone, G (1996) Il trattamento chirurgico

Skarsgard, E.D.; Atkinson, K.G.; Bell, G.A.; Pezim, M.E.; Seal, A.M. & Sharo, F.R. (1989)

Stonnington, C.M.; Phillips, S.F.; Melton, L.J. & Zinsmeister, A.R. (1987) Chronic ulcerative

Taylor, B.A.; Pemberton, J.H.; Carpenter, H.A.; Levin, K.E.; Schroeder, K.W.; Welling, D.R.;

Truelove, S.C. & Jewell, D.P. (1974) Intensive intravenous regimen for severe attack of

Truelove, S.C. & Witts, L.J. (1955) Cortisone in ulcerative colitis: final report on a therapeutic

Turnbull, R.B.; Hawk, W.A. & Weakly, F.I. (1971) Surgical treatment of toxic megacolon:

Utsonomiya, A.J.; Iwama, T.; Iamjo, M.; Matsuo, S.; Sawai, S.; Yalgashi, K. & Hirayama, R.

van Heerden, J.A. & Beart, R.W. Jr (1980) Carcinoma of the colon and rectum complicating

Williams, N.S. (1989) Restorative proctocolectomy is the first choice elective surgical

Williams, N.S. & Johnston, D (1985) The current state of mucosal proctectomy and ileo-anal

Ziv, Y.; Fazio, V.W.; Church, J.M.; Milsom, J.W. & Schroeder, T.K. (1995) Safety of urgent

chronic ulcerative colitis. *Dis Colon Rectum* 23: 155-159

treatment for ulcerative colitis. *Br J Surg* 76: 1109

ileostomy and colostomy to prepare patients for colectomy. *Am J Surg* 122: 325-331

(1980) Total Colectomy, mucosal proctectomy and ileoanal anastomosis. *Dis Colon* 

anastomosis in the surgical treatment of ulcerative colitis and familial polyposis. *Br* 

restorative proctocolectomy with ileal pouch-anal anastomosis for fulminant colitis.

implications for colonoscopic surveillance. *Dis Colon Rectum* 35: 950-956 Truelove, S.C. (1988) Medical management of ulcerative colitis and indication for colectomy.

colitis: incidence and prevalence in a community. *Gut* 28: 402-409

della rettocolite ulcerosa. *Tecniques in Coloproctol.* 4: 98-101

colitis and for polyposis. *Am J Surg* 157: 457-471

584-592

12:e172

*Surg.* 76:428-435

*Worl J Surg.* 12: 142-147

trial. *Br Med J 2*:1041-1048

*Rectum* 23: 459-466

*J Surg.* 72: 159-168

*Dis Colon Rectum*, 38: 345-349

ulcerative colitis. *Lancet* i: 1067-1074

*Atti della Soc.Ital. Chir.* 3: 144-160

Quality of life after restorative proctocolectomy with a pelvic pouch compares favourably with that of patients with medically treated colitis. *Dis Colon Rectum.* 36:

Randomized, controlled trial to compare the J-pouch and W-pouch configurations

after stapled haemorrhoidopexy for unrecognized ulcerative colitis. *Colorectal Dis.* 

M. & Riegler, G. (2010b) The effect of pelvic septic complications on function and quality of life after ileal pouch-anal anastomosis: a single center experience. *Am* 

Function and quality of life results after ileal pouch surgery for chronic ulcerative

Spencer, M.P. & Zinsmeister, A.R. (1992) Dysplasia in chronic ulcerative colitis:

Ulcerative colitis is occasionally exacerbated by fulminant manifestation of colitis. Severe ulcerative colitis is usually defined based on Trulove and Witts' criteria (Table 1) (Truelove & Witts, 1955). The incidence of severe colitis in ulcerative colitis is 5 to 15 percent (Chen et al., 1998). If the patient is not improving despite intensive medical therapy, emergency colectomy is mandatory. In such a case, the patient is often malnourished and anemic, and has received high dose of steroids; therefore, the usual option in patients with severe ulcerative colitis is subtotal colectomy and ileostomy with preservation of the rectum (Gurland & Wexner, 2002). Restorative proctectomy can be done at a later time after the patient has recovered fully and steroids have been withdrawn (Fig. 1).


Table 1. Definition of severe ulcerative colitis based on Trulove and Witts' criteria (Truelove & Witts, 1955). When criteria (1) and (2) are applied, either criterion (3) or (4) is applied, and four of the six criteria are applied, the ulcerative colitis is diagnosed as severe

The earliest reports of the laparoscopic approach to ulcerative colitis in the elective setting are from the early 1990s (Peters, 1992; Wexner et al., 1992). These first results did not seem very promising, the laparoscopic technique appeared too difficult to apply, too timeconsuming, and comorbidity was high. The authors discouraged the use of laparoscopic approach for patients requiring total colectomy. However, with advances in technology and

Laparoscopic Surgery for Severe Ulcerative Colitis 17

Lap Open Lap Open *P*-value Lap

(min)

330 225 <0.001 0

483 402 <0.05 0


UC: ulcerative colitis, FAP: familial ademnomatous polyposis



Conversion (%)

(year) Number of patients Operative time

20 (UC;13 FAP;7)

13 (UC;6 FAP;7)

33 (UC;31 FAP;2)

proctocolectomy and ileo-anal anastomosis in elective setting

Table 2. Perioperative data from clinical trials treating laparoscopic-assisted restorative

Lap Open *P*-value Lap Open *P*-value

Marcello 7 8 0.02 20 25 NS

Hashimoto 24.1 31.3 <0.05 55 38 0.453

Gill 7 - - 29 - -

Kienle 12 - - 30 - -

Larson - - - 6 12 0.39

Table 2 (continued). Perioperative data from clinical trials treating laparoscopic-assisted

restorative proctocolectomy and ileo-anal anastomosis in elective setting

Author Hospital stay (days) Morbidity (%)

Author

Marcello (2000)

Hashimoto (2001)

> Gill (2004)

Kienle (2005)

Larson (2005)

20 (UC;13 FAP;7)

11 (UC;6 FAP;5)

14 (UC;13 FAP;1)

50 (UC;23 FAP;27)

33 (UC;31 FAP;2)

experience of laparoscopic surgery, more favourable results have been stated (Marcello et al., 2000; Brown et al., 2001; Hamel et al., 2001; Hashimoto et al., 2001; Seshadri et al., 2001; Ky et al., 2002; Gill et al., 2004; Kienle et al., 2005; Larson et al., 2005). These reports have shown the advantages of laparoscopic total colectomy such as reduced postoperative pain, earlier return of intestinal function, decreased length of hospital stay, and improved cosmesis (Table 2). On the basis of these results, recent studies have evaluated the feasibility and safety of minimally invasive surgery for selected patients with severe ulcerative colitis. Minimally invasive surgery techniques include laparoscopic-assisted colectomy and handassisted laparoscopic surgery. In this article, an overview of current status of minimally invasive surgery to severe ulcerative colitis is provided.

Fig. 1. Three-stage restorative proctocolectomy for severe ulcerative colitis

experience of laparoscopic surgery, more favourable results have been stated (Marcello et al., 2000; Brown et al., 2001; Hamel et al., 2001; Hashimoto et al., 2001; Seshadri et al., 2001; Ky et al., 2002; Gill et al., 2004; Kienle et al., 2005; Larson et al., 2005). These reports have shown the advantages of laparoscopic total colectomy such as reduced postoperative pain, earlier return of intestinal function, decreased length of hospital stay, and improved cosmesis (Table 2). On the basis of these results, recent studies have evaluated the feasibility and safety of minimally invasive surgery for selected patients with severe ulcerative colitis. Minimally invasive surgery techniques include laparoscopic-assisted colectomy and handassisted laparoscopic surgery. In this article, an overview of current status of minimally

invasive surgery to severe ulcerative colitis is provided.

Fig. 1. Three-stage restorative proctocolectomy for severe ulcerative colitis


UC: ulcerative colitis, FAP: familial ademnomatous polyposis

Table 2. Perioperative data from clinical trials treating laparoscopic-assisted restorative proctocolectomy and ileo-anal anastomosis in elective setting


Table 2 (continued). Perioperative data from clinical trials treating laparoscopic-assisted restorative proctocolectomy and ileo-anal anastomosis in elective setting

Laparoscopic Surgery for Severe Ulcerative Colitis 19

studies, patients with complications such as toxic megacolon, intestinal perforation, peritonitis,

Lap Open Lap Open *P*-value Lap

(UC;27 CD;8) - 252 - - 6

220 ~ 360

( 2010) 29 61 216 170 <0.01 7

(2008) 32 - 135 - - 3

48 (UC;14 CD;29 IC;5)

22 (UC;27 CD;5)

Table 4. Perioperative data from clinical trials treating laparoscopic-assisted subtotal

Telem *et al* (Telem et al., 2010) from the Mount Sinai Medical Center, New York City evaluated laparoscopic-assisted subtotal colectomy (*n*=29) versus open subtotal colectomy (*n*=61) in patients with ulcerative colitis requiring urgent or emergent operative intervention. Two (7%) patients in the laparoscopic group required conversion to open surgery. The mean operative time was significantly longer in the laparoscopic group (216.4 vs. 169.9 min, *P*<0.01). Intraoperative blood loss was significantly lower in the laparoscopic group (130.4 vs. 201.4 ml, *p*<0.05). The mean hospital stay was shorter in laparoscopic group (4.53 vs. 6 days, *p*<0.001). The rate of wound complication was significantly lower in laparoscopic

Maggiori *et al* (Maggiori et al., 2010) from Beaujon Hospital, France evaluated the outcome of laparoscopic-assisted subtotal colectomy with double end ileo-sigmoidostomy in patients with acute or severe colitis. The medical records of 35 patients (Ulcerative colitis, *n*=27; Crohn's disease, *n*=8) were reviewed. Two (6%) patients required conversion to open surgery because of intra-abdominal adhesions (n=1), and complicated case with perforated acute colitis (n=1). The mean operative time was 252 minutes. The mean hospital stay was 8 days. Five (15%) patients experienced postoperative complications and no reoperation was needed. With a mean delay of 80 ± 20 days (range: 43 to 129 days), intestinal continuity was

Fowkes *et al* (Fowkes et al., 2008) from Frenchay Hospital, United Kingdom analyzed surgical outcomes of fulminate and medically resistant ulcerative colitis carried out

(min)

253 231 NS 5

271 150 <0.001 0

UC: ulcerative colitis, FAP: familial ademnomatous polyposis


Conversion (%)

or shock status were excluded from the indication for minimally invasive surgery.

(year) Number of patients Operative time

Author

Telem

Maggiori (2010)

Fowkes

Maeceau (2007)

Bell

Dunker (2000)

35

40 (UC;26CD;13 IC;1)

(2002) 18 6

colectomy for severe ulcerative colitis

group (0 vs. 21 percent, *p*<0.01).

restored in 100 percent of the cases.

10 (UC;8 CD;2)


Table 2 (continued). Perioperative data from clinical trials treating laparoscopic-assisted restorative proctocolectomy and ileo-anal anastomosis in elective setting

#### **2. Indication for minimally invasive surgery in severe ulcerative colitis**

Patients are usually hospitalized and received intensive medical therapy when their severe colitis is diagnosed. The mainstay of treatment for severe ulcerative colitis is Truelove's intensive intravenous steroid regimen (Truelove & Jewell 1974). Immunosuppressive therapy, cytapheresis therapy, and/or steroid pulse therapy are considered as alternative treatment options (Lichtiger et al., 1994; Sawada et al., 1995; Sood et al., 2002). Total parenteral nutrition, albumin and blood transfusion, and/or antibiotic therapy are considered as supportive therapies. Surgery is indicated when the patients are unresponsive to medical therapy, or when massive hemorrhage, toxic megacolon, or perforation occurs. Patients with severe ulcerative colitis are often malnourished and anemic, and has received high dose of steroids, which increase the likelihood of postoperative complications.

Minimally invasive surgery for severe ulcerative colitis is technically difficult because of active inflammation and induration of the mesentery, fragile intestinal tissue, abscesses between intestinal loops, and dense adhesions. To date, there is no randomized controlled trial assessing minimally invasive surgery for severe ulcerative colitis. In most retrospective studies, the patients with complications such as toxic megacolon, intestinal perforation, peritonitis, or shock stage were excluded from the indication for minimally invasive surgery (Table 3).


Table 3. Exclusion criteria for minimally invasive surgery in severe ulcerative colitis

#### **3. Laparoscopic-assisted subtotal colectomy for severe ulcerative colitis**

Several recent studies have reported the outcome of laparoscopic-assisted subtotal colectomy in selected patients with severe ulcerative colitis (Table 4). In most of these

Complication rates were similar to open surgery.

Gill Technically feasible. Operative time was acceptable.

restorative proctocolectomy and ileo-anal anastomosis in elective setting

Hashimoto Better cosmetic results. Reduce the degree of postoperative pain. Shorter

Kienle Technically feasible. LAP may reduce the need for perioperative blood

Larson The function and quality of life outcomes seemed to be equivalent to open

Table 2 (continued). Perioperative data from clinical trials treating laparoscopic-assisted

Patients are usually hospitalized and received intensive medical therapy when their severe colitis is diagnosed. The mainstay of treatment for severe ulcerative colitis is Truelove's intensive intravenous steroid regimen (Truelove & Jewell 1974). Immunosuppressive therapy, cytapheresis therapy, and/or steroid pulse therapy are considered as alternative treatment options (Lichtiger et al., 1994; Sawada et al., 1995; Sood et al., 2002). Total parenteral nutrition, albumin and blood transfusion, and/or antibiotic therapy are considered as supportive therapies. Surgery is indicated when the patients are unresponsive to medical therapy, or when massive hemorrhage, toxic megacolon, or perforation occurs. Patients with severe ulcerative colitis are often malnourished and anemic, and has received

**2. Indication for minimally invasive surgery in severe ulcerative colitis** 

high dose of steroids, which increase the likelihood of postoperative complications.

Table 3. Exclusion criteria for minimally invasive surgery in severe ulcerative colitis

**3. Laparoscopic-assisted subtotal colectomy for severe ulcerative colitis** 

Several recent studies have reported the outcome of laparoscopic-assisted subtotal colectomy in selected patients with severe ulcerative colitis (Table 4). In most of these

Minimally invasive surgery for severe ulcerative colitis is technically difficult because of active inflammation and induration of the mesentery, fragile intestinal tissue, abscesses between intestinal loops, and dense adhesions. To date, there is no randomized controlled trial assessing minimally invasive surgery for severe ulcerative colitis. In most retrospective studies, the patients with complications such as toxic megacolon, intestinal perforation, peritonitis, or shock stage were excluded from the indication for minimally invasive surgery

Technically feasible and safe. Shorter hospital stay. Quicker return of bowel

Author Conclusion

function.

hospital stay.

transfusion.

(1) Toxic megacolon

(3) Peritonitis (4) Shock status

(2) Intestinal perforation

surgery.

Marcello

(Table 3).


studies, patients with complications such as toxic megacolon, intestinal perforation, peritonitis, or shock status were excluded from the indication for minimally invasive surgery.

UC: ulcerative colitis, FAP: familial ademnomatous polyposis

Table 4. Perioperative data from clinical trials treating laparoscopic-assisted subtotal colectomy for severe ulcerative colitis

Telem *et al* (Telem et al., 2010) from the Mount Sinai Medical Center, New York City evaluated laparoscopic-assisted subtotal colectomy (*n*=29) versus open subtotal colectomy (*n*=61) in patients with ulcerative colitis requiring urgent or emergent operative intervention. Two (7%) patients in the laparoscopic group required conversion to open surgery. The mean operative time was significantly longer in the laparoscopic group (216.4 vs. 169.9 min, *P*<0.01). Intraoperative blood loss was significantly lower in the laparoscopic group (130.4 vs. 201.4 ml, *p*<0.05). The mean hospital stay was shorter in laparoscopic group (4.53 vs. 6 days, *p*<0.001). The rate of wound complication was significantly lower in laparoscopic group (0 vs. 21 percent, *p*<0.01).

Maggiori *et al* (Maggiori et al., 2010) from Beaujon Hospital, France evaluated the outcome of laparoscopic-assisted subtotal colectomy with double end ileo-sigmoidostomy in patients with acute or severe colitis. The medical records of 35 patients (Ulcerative colitis, *n*=27; Crohn's disease, *n*=8) were reviewed. Two (6%) patients required conversion to open surgery because of intra-abdominal adhesions (n=1), and complicated case with perforated acute colitis (n=1). The mean operative time was 252 minutes. The mean hospital stay was 8 days. Five (15%) patients experienced postoperative complications and no reoperation was needed. With a mean delay of 80 ± 20 days (range: 43 to 129 days), intestinal continuity was restored in 100 percent of the cases.

Fowkes *et al* (Fowkes et al., 2008) from Frenchay Hospital, United Kingdom analyzed surgical outcomes of fulminate and medically resistant ulcerative colitis carried out

Laparoscopic Surgery for Severe Ulcerative Colitis 21

Bell *et al* (Bell & Seymour 2002) from Yale University School of Medicine, New Haven reported surgical outcomes of fulminant ulcerative colitis carried out laparoscopically. The medical records of 18 patients with poorly controlled fulminant ulcerative colitis on aggressive immunosuppressive therapy who underwent laparoscopic subtotal colectomy were reviewed. None of the laparoscopic procedures required conversion to an open operation, and there were no intraoperative complications. The total operative time ranged from 220 to 360 min. Procedure length diminished significantly over the course of the series; the operative time during the last six procedures was 244 vs. 275 minutes during the prior 12 patients. Postoperative hospital stay was 5.0 days vs. 8.8 days (*p*<0.05) for a group of 6 patients who had undergone open subtotal colectomy for the same indications.

> Technically feasible and safe. Improved cosmesis. Reduced intraoperative blood loss. Negligible wound complications. Shorter hospital stay.

> Operative time, overall morbidity, and hospital stay were similar to open

Low morbidity. Facilitated second step of intestinal continuity restoration for

Postoperative complications occurred in 6 (33%) patients.

(year) Conclusions

both ileorectal and ileo-anal anastomosis.

Technically feasible. Shorter hospital stay.

Technically feasible and safe. Shorter hospital stay.

Facilitated subsequent proctectomy and pouch construction.

84% of the patients underwent restorative intestinal continuity

Facilitated subsequent proctectomy and pouch construction.

Table 4 (continued). Perioperative data from clinical trials treating laparoscopic-assisted

**4. Hand-assisted laparoscopic subtotal colectomy for severe ulcerative** 

Standard laparoscopic assisted subtotal colectomy for severe ulcerative colitis is still technically difficult because of bowel friability and hypervascularity, creating a high

(2000) Technically feasible and safe. Shorter hospital stay. Longer operative time.

Dunker et al (Dunker et al., 2000) from Academic Medical Center, Netherlands evaluated the feasibility and safety of emergency laparoscopic-assisted subtotal colectomy in patients with severe acute colitis. The medical records of 42 consecutive patients (Laparoscopic group; *n*=10, Open group; *n*=32) were reviewed. No patients in laparoscopic group required conversion to open surgery. The mean operative time was longer in laparoscopic group than in the open group (271 vs. 150 minutes). Postoperative hospital stay was significantly shorter in the laparoscopic group than in the open group (14.6 vs. 18.0 days. Complications were similar for the two groups. They concluded that laparoscopic-assisted subtotal colectomy in patients with severe acute colitis was feasible and safe as open colectomy.

Author

Telem (2010)

Maggiori (2010)

Fowkes (2008)

Marceau (2007)

> Bell (2002)

Dunker

**colitis** 

surgery.

subtotal colectomy for severe ulcerative colitis

laparoscopically. The medical records of 32 patients were reviewed. One (3%) patient required conversion to open surgery because of a small, localized perforation (unsuspected preoperatively). The median operative time was 135 minutes. The median hospital stay was 8 days. Twelve (38%) patients experienced postoperative complications. They concluded that laparoscopic-assisted subtotal colectomy in fulminant and medically resistant ulcerative colitis was feasible, safe and largely predictable operations that allow for early hospital discharge.


Table 4 (continued). Perioperative data from clinical trials treating laparoscopic-assisted subtotal colectomy for severe ulcerative colitis

Marceau *et al* (Marceau et al., 2007) from Beaujon Hospital, France conducted a casematched study to assess the feasibility and safety of laparoscopic-assisted subtotal colectomy (*n*=40) (Ulcerative colitis, n=14; Crohn's disease, n=29; Indeterminate colitis, n=5) compared with open subtotal colectomy (*n*=48) (Ulcerative colitis, n=26; Crohn's disease, n=13; Indeterminate colitis, n=1) in patients with severe colitis. Two (5%) patients required conversion to open surgery because of intensive adhesions (*n*=1) and colonic fistula (*n*=1). Between the laparoscopic group and open group, the mean operative time (253 vs. 231 min), overall morbidity (35 vs. 56%), and hospital stay (9 vs. 12 days) were similar. After a followup of 3 ± 4 months after the first operation, 35 patients (88%) have had restorative intestinal continuity through laparoscopic approach or elective incision at the site of previous stoma. They concluded that laparoscopic-assisted subtotal colectomy was as safe and effective as open subtotal colectomy for patients with severe colitis complicating inflammatory bowel disease.

laparoscopically. The medical records of 32 patients were reviewed. One (3%) patient required conversion to open surgery because of a small, localized perforation (unsuspected preoperatively). The median operative time was 135 minutes. The median hospital stay was 8 days. Twelve (38%) patients experienced postoperative complications. They concluded that laparoscopic-assisted subtotal colectomy in fulminant and medically resistant ulcerative colitis was feasible, safe and largely predictable operations that allow for early hospital discharge.

Lap Open *P*-value Lap Open *P*-value

(2010) 8 - - 15 - -

(2008) 8 - - 38 - -

(2002) 5.1 8.8 <0.05 33 - -

Table 4 (continued). Perioperative data from clinical trials treating laparoscopic-assisted

Marceau *et al* (Marceau et al., 2007) from Beaujon Hospital, France conducted a casematched study to assess the feasibility and safety of laparoscopic-assisted subtotal colectomy (*n*=40) (Ulcerative colitis, n=14; Crohn's disease, n=29; Indeterminate colitis, n=5) compared with open subtotal colectomy (*n*=48) (Ulcerative colitis, n=26; Crohn's disease, n=13; Indeterminate colitis, n=1) in patients with severe colitis. Two (5%) patients required conversion to open surgery because of intensive adhesions (*n*=1) and colonic fistula (*n*=1). Between the laparoscopic group and open group, the mean operative time (253 vs. 231 min), overall morbidity (35 vs. 56%), and hospital stay (9 vs. 12 days) were similar. After a followup of 3 ± 4 months after the first operation, 35 patients (88%) have had restorative intestinal continuity through laparoscopic approach or elective incision at the site of previous stoma. They concluded that laparoscopic-assisted subtotal colectomy was as safe and effective as open subtotal colectomy for patients with severe colitis complicating inflammatory bowel

28

34

NS

<0.01

(<0.10)

0.41

1.00

Wound complication 21

Minor complication2 5

Major complication2 8

Wound complication 0

Minor complication 10

Major complication 30

(<0.10) 35 56 NS

(year) Hospital stay (days) Morbidity (%)

Author

Telem

Maggiori

Fowkes

Maeceau

Bell

Dunker

disease.

(2010) 4.5 6 <0.001

(2007) 9 12 NS

(2000) 14.6 18.0 0.05

subtotal colectomy for severe ulcerative colitis

Bell *et al* (Bell & Seymour 2002) from Yale University School of Medicine, New Haven reported surgical outcomes of fulminant ulcerative colitis carried out laparoscopically. The medical records of 18 patients with poorly controlled fulminant ulcerative colitis on aggressive immunosuppressive therapy who underwent laparoscopic subtotal colectomy were reviewed. None of the laparoscopic procedures required conversion to an open operation, and there were no intraoperative complications. The total operative time ranged from 220 to 360 min. Procedure length diminished significantly over the course of the series; the operative time during the last six procedures was 244 vs. 275 minutes during the prior 12 patients. Postoperative hospital stay was 5.0 days vs. 8.8 days (*p*<0.05) for a group of 6 patients who had undergone open subtotal colectomy for the same indications. Postoperative complications occurred in 6 (33%) patients.


Table 4 (continued). Perioperative data from clinical trials treating laparoscopic-assisted subtotal colectomy for severe ulcerative colitis

Dunker et al (Dunker et al., 2000) from Academic Medical Center, Netherlands evaluated the feasibility and safety of emergency laparoscopic-assisted subtotal colectomy in patients with severe acute colitis. The medical records of 42 consecutive patients (Laparoscopic group; *n*=10, Open group; *n*=32) were reviewed. No patients in laparoscopic group required conversion to open surgery. The mean operative time was longer in laparoscopic group than in the open group (271 vs. 150 minutes). Postoperative hospital stay was significantly shorter in the laparoscopic group than in the open group (14.6 vs. 18.0 days. Complications were similar for the two groups. They concluded that laparoscopic-assisted subtotal colectomy in patients with severe acute colitis was feasible and safe as open colectomy.

#### **4. Hand-assisted laparoscopic subtotal colectomy for severe ulcerative colitis**

Standard laparoscopic assisted subtotal colectomy for severe ulcerative colitis is still technically difficult because of bowel friability and hypervascularity, creating a high

Laparoscopic Surgery for Severe Ulcerative Colitis 23

and needed resuture of the wound. In the hand-assisted surgery group, 4 of 30 patients (13%) had surgical site infection, but no patient developed wound dehiscence. The authors concluded that hand-assisted laparoscopic surgery can be an alternative to conventional

conversion to open surgery was 2 (5.5%) in laparoscopic-assisted surgery group, and 1 (7.1%) in hand-assisted laparoscopic surgery group, respectively. The median operative time was 251 minutes. The median hospital stay was 4 days. Seventeen (34%) patients experienced postoperative complications and 2 (4%) patients required reoperation. The most frequent complications after each procedure were ileus (8%) and surgical site infections (4%).

12 mm

5-12 mm

70 mm

5-12 mm (Optional)

Fig. 2. Port and incision placement for hand-assisted laparoscopic subtotal colectomy (above). Operative scars after hand-assisted laparoscopic subtotal colectomy (below)

open surgery for severe ulcerative colitis.

likelihood of perforation and bleeding. Hand-assisted laparoscopic surgery is a technique in which laparoscopic procedures are performed with the aid of a hand inserted into the abdomen through a small incision. (Ballantyne & Leahy, 2004; Nakajima et al., 2004; Rivadeneira et al., 2004; Boushey et al., 2007). Surgeons are abled to obtain tactile sensation, manual retraction, and digital vascular control, which could allow complex laparoscopic operations to be performed more effectively and satisfactorily. A few recent studies have reported hand-assisted laparoscopic subtotal colectomy for selected patients with severe ulcerative colitis (Watanabe et al., 2009; Holubar et al., 2009; Chung et al., 2009).

#### **4.1 Surgical technique for hand-assisted laparoscopic subtotal colectomy**

The patient was placed in the supine position with legs moderately opened. A 70-mm lower paramedian incision was made and the abdomen was entered (Fig. 2). The ascending and descending colon was manually mobilized through the incision. After the mobilization, the hand port was placed in the lower paramedian incision. A 12-mm trocar was inserted above the umbilicus for laparoscope and pneumoperitoneum. A 5-mm or 12-mm trocar was inserted in the lower left abdomen for dissection. If necessary, the third 5-mm or 12-mm trocar was inserted in the upper left abdomen. The greater omentum was dissected and splenocolic and hepatocolic ligaments were taken down to mobilize the transverse colon by use of a Harmonic ScalpelTM (UltraCision, Smithfield, RI) or LigaSureTM (Tyco Healthcare Japan, Tokyo, Japan) (Fig.3, 4). The mesocolon was also dissected. The ileocolic artery was preserved in all patients to provide optimal blood supply to the distal ileum. After this, the laparoscopic procedure was ended. Transsection of the terminal ileum and proximal rectum were performed with a linear stapler, and the colon was taken out through the lower paramedian incision. A mucous fistula of the rectum was constructed in the left lower abdomen, and a standard Brooke ileostomy was fashioned in the right lower abdomen (Fig. 5).

#### **4.2 Hand-assisted laparoscopic surgery for severe ulcerative colitis**

A few recent studies have evaluated the outcome of hand-assisted laparoscopic subtotal colectomy in patients with severe ulcerative colitis.

The authors (Watanabe et al., 2009) from Tohoku University Graduate School of Medicine, Japan recently reviewed the medical records of 60 patients who underwent emergency subtotal colectomy with hand-assisted laparoscopic technique (*n*=30) or conventional open technique (*n*=30) for severe ulcerative colitis. One (3%) patient in the laparoscopic group required conversion to open surgery because of excessive inflammatory adhesion. The median operative time was significantly longer in the hand-assisted laparoscopic surgery group than in the open surgery group (242 vs. 191 minutes; *P*<0.001). The median time to first solid diet in the hand-assisted laparoscopic surgery group was significantly shorter than that in the open surgery group (4.8 vs. 5.9 days; *P*=0.007). The postoperative hospital stay in the hand-assisted laparoscopic surgery group was significantly shorter than in the open surgery group (23.0 vs. 33.0 days; *P*=0.001). The number of postoperative complications during the hospital stay in the hand-assisted laparoscopic surgery group was significantly less than in open surgery group (37 vs. 63%; *P* = 0.041). Four (13%) patients in the open surgery group required relaparotomy because of peritoneal abscess (two patients) or strangulation ileus (two patients), but no patients needed relaparotomy in the handassisted laparoscopic surgery group (*P*=0.040). In the open surgery group, 4 of 30 patients (13%) had surgical site infection and 2 patients among them developed wound dehiscence

likelihood of perforation and bleeding. Hand-assisted laparoscopic surgery is a technique in which laparoscopic procedures are performed with the aid of a hand inserted into the abdomen through a small incision. (Ballantyne & Leahy, 2004; Nakajima et al., 2004; Rivadeneira et al., 2004; Boushey et al., 2007). Surgeons are abled to obtain tactile sensation, manual retraction, and digital vascular control, which could allow complex laparoscopic operations to be performed more effectively and satisfactorily. A few recent studies have reported hand-assisted laparoscopic subtotal colectomy for selected patients with severe

The patient was placed in the supine position with legs moderately opened. A 70-mm lower paramedian incision was made and the abdomen was entered (Fig. 2). The ascending and descending colon was manually mobilized through the incision. After the mobilization, the hand port was placed in the lower paramedian incision. A 12-mm trocar was inserted above the umbilicus for laparoscope and pneumoperitoneum. A 5-mm or 12-mm trocar was inserted in the lower left abdomen for dissection. If necessary, the third 5-mm or 12-mm trocar was inserted in the upper left abdomen. The greater omentum was dissected and splenocolic and hepatocolic ligaments were taken down to mobilize the transverse colon by use of a Harmonic ScalpelTM (UltraCision, Smithfield, RI) or LigaSureTM (Tyco Healthcare Japan, Tokyo, Japan) (Fig.3, 4). The mesocolon was also dissected. The ileocolic artery was preserved in all patients to provide optimal blood supply to the distal ileum. After this, the laparoscopic procedure was ended. Transsection of the terminal ileum and proximal rectum were performed with a linear stapler, and the colon was taken out through the lower paramedian incision. A mucous fistula of the rectum was constructed in the left lower abdomen, and a standard Brooke ileostomy was fashioned in the right lower abdomen (Fig. 5).

A few recent studies have evaluated the outcome of hand-assisted laparoscopic subtotal

The authors (Watanabe et al., 2009) from Tohoku University Graduate School of Medicine, Japan recently reviewed the medical records of 60 patients who underwent emergency subtotal colectomy with hand-assisted laparoscopic technique (*n*=30) or conventional open technique (*n*=30) for severe ulcerative colitis. One (3%) patient in the laparoscopic group required conversion to open surgery because of excessive inflammatory adhesion. The median operative time was significantly longer in the hand-assisted laparoscopic surgery group than in the open surgery group (242 vs. 191 minutes; *P*<0.001). The median time to first solid diet in the hand-assisted laparoscopic surgery group was significantly shorter than that in the open surgery group (4.8 vs. 5.9 days; *P*=0.007). The postoperative hospital stay in the hand-assisted laparoscopic surgery group was significantly shorter than in the open surgery group (23.0 vs. 33.0 days; *P*=0.001). The number of postoperative complications during the hospital stay in the hand-assisted laparoscopic surgery group was significantly less than in open surgery group (37 vs. 63%; *P* = 0.041). Four (13%) patients in the open surgery group required relaparotomy because of peritoneal abscess (two patients) or strangulation ileus (two patients), but no patients needed relaparotomy in the handassisted laparoscopic surgery group (*P*=0.040). In the open surgery group, 4 of 30 patients (13%) had surgical site infection and 2 patients among them developed wound dehiscence

ulcerative colitis (Watanabe et al., 2009; Holubar et al., 2009; Chung et al., 2009).

**4.1 Surgical technique for hand-assisted laparoscopic subtotal colectomy** 

**4.2 Hand-assisted laparoscopic surgery for severe ulcerative colitis** 

colectomy in patients with severe ulcerative colitis.

and needed resuture of the wound. In the hand-assisted surgery group, 4 of 30 patients (13%) had surgical site infection, but no patient developed wound dehiscence. The authors concluded that hand-assisted laparoscopic surgery can be an alternative to conventional open surgery for severe ulcerative colitis.

conversion to open surgery was 2 (5.5%) in laparoscopic-assisted surgery group, and 1 (7.1%) in hand-assisted laparoscopic surgery group, respectively. The median operative time was 251 minutes. The median hospital stay was 4 days. Seventeen (34%) patients experienced postoperative complications and 2 (4%) patients required reoperation. The most frequent complications after each procedure were ileus (8%) and surgical site infections (4%).

Fig. 2. Port and incision placement for hand-assisted laparoscopic subtotal colectomy (above). Operative scars after hand-assisted laparoscopic subtotal colectomy (below)

Laparoscopic Surgery for Severe Ulcerative Colitis 25

Fig. 4. Mobilization of the transverse colon using hand-assisted laparoscopic technique. Splenocolic ligament was taken down from the transverse colon to the descending colon

Fig. 3. Mobilization of the transverse colon using hand-assisted laparoscopic technique. Splenocolic ligament was taken down from the descending colon to the transverse colon

Fig. 3. Mobilization of the transverse colon using hand-assisted laparoscopic technique. Splenocolic ligament was taken down from the descending colon to the transverse colon

Fig. 4. Mobilization of the transverse colon using hand-assisted laparoscopic technique. Splenocolic ligament was taken down from the transverse colon to the descending colon

Laparoscopic Surgery for Severe Ulcerative Colitis 27

*al* (Chung et al., 2009) from Washington University School of Medicine, St. Louis compared short-term outcomes of minimally invasive vs. open subtotal colectomy for severe ulcerative colitis. The medical records of 81 patients (Laparoscopic-assisted surgery; *n*=17, Handassisted laparoscopic surgery; *n*=20, Open surgery; *n*=44) were reviewed. Two (11.8%) patients in minimally invasive surgery group required conversion to open surgery because of bleeding from the middle colic vessels, and colonic injury with feculent spillage. Intraoperative intravenous fluid volume, operative time, and estimated blood loss were increased in the minimally invasive surgery group. Short-term recovery (return of bowel function, length of stay, inpatient narcotic use, and complication rate) was significantly lessened in the minimally invasive surgery group. The minimally invasive surgery group completed all three stages a mean of 66 days sooner than the open surgery group (188.9 vs.

MIS Open MIS Open *P*-value MIS

LAP;36 - 251 - - HALS;7.1

LAP;17 44 223 140 <0.001 Overall;

MIS Open *P*-value MIS Open *P*-value

(2009) 23 33 0.001 37 63 0.041

(2009) 4 - - 34 - -

(2009) 4.9 8.5 0.039 24 48 0.039

Table 5 (Continued). Perioperative data from clinical trials treating laparoscopic-assisted

(2009) HALS;30 30 242 191 <0.001 3

Table 5. Perioperative data from clinical trials treating laparoscopic-assisted subtotal

(year) Hospital stay (days) Morbidity (%)

(min) Conversion (%)

LAP;5.5

11.8

MIS: minimally invasive surgery

MIS: minimally invasive surgery

(year) Number of patients Operative time

255.36 days, P = 0.0038).

Author

Watanabe

Holubar (2009)

Chung (2009)

Author

Watanabe

Holubar

Chung

HALS;14

HALS;20

subtotal colectomy for severe ulcerative colitis

colectomy for severe ulcerative colitis

Fig. 5. Operative scars after three-stage hand-assisted laparoscopic proctocolectomy

Holubar *et al* (Holubar et al., 2009) from Mayo Clinic, Rochester evaluated the safety and feasibility of minimally invasive subtotal colectomy for fulminant ulcerative colitis. The medical records of 50 patients (Laparoscopic-assisted surgery; n=36, Hand-assisted laparoscopic surgery; n=14) were reviewed. The number of patients who required Chung *et* 

Fig. 5. Operative scars after three-stage hand-assisted laparoscopic proctocolectomy

Holubar *et al* (Holubar et al., 2009) from Mayo Clinic, Rochester evaluated the safety and feasibility of minimally invasive subtotal colectomy for fulminant ulcerative colitis. The medical records of 50 patients (Laparoscopic-assisted surgery; n=36, Hand-assisted laparoscopic surgery; n=14) were reviewed. The number of patients who required Chung *et*  *al* (Chung et al., 2009) from Washington University School of Medicine, St. Louis compared short-term outcomes of minimally invasive vs. open subtotal colectomy for severe ulcerative colitis. The medical records of 81 patients (Laparoscopic-assisted surgery; *n*=17, Handassisted laparoscopic surgery; *n*=20, Open surgery; *n*=44) were reviewed. Two (11.8%) patients in minimally invasive surgery group required conversion to open surgery because of bleeding from the middle colic vessels, and colonic injury with feculent spillage. Intraoperative intravenous fluid volume, operative time, and estimated blood loss were increased in the minimally invasive surgery group. Short-term recovery (return of bowel function, length of stay, inpatient narcotic use, and complication rate) was significantly lessened in the minimally invasive surgery group. The minimally invasive surgery group completed all three stages a mean of 66 days sooner than the open surgery group (188.9 vs. 255.36 days, P = 0.0038).


MIS: minimally invasive surgery

Table 5. Perioperative data from clinical trials treating laparoscopic-assisted subtotal colectomy for severe ulcerative colitis


MIS: minimally invasive surgery

Table 5 (Continued). Perioperative data from clinical trials treating laparoscopic-assisted subtotal colectomy for severe ulcerative colitis

Laparoscopic Surgery for Severe Ulcerative Colitis 29

Ballantyne, G. H. & Leahy, P.F. (2004). Hand-assisted laparoscopic colectomy: evolution to a

Bell, R. L. & Seymour, N. E. (2002). Laparoscopic treatment of fulminant ulcerative colitis.

Boushey, R. P, Marcello, P. W., Martel, G., Rusin, L. C., Roberts, P. L., & Schoetz, D. J., Jr.

Brown, S. R., Eu K. W., & Seow-Choen, F. (2001). Consecutive series of laparoscopic-assisted vs. minilaparotomy restorative proctocolectomies. *Dis Colon Rectum* 44(3): 397-400. Chen, H. H., Wexner, S. D., Weiss, E. G., Nogueras, J. J., Alabaz, O., Iroatulam, A. J., Nessim,

Chung, T.P., Fleshman, J.W., Birnbaum, E.H., Hunt, S.R., Dietz, D.W., Read, T.E., & Mutch,

Dunker, M. S., Bemelman, W. A., Slors, J. F., van Hogezand, R. A., Ringers, J., & Gouma, D.

Fowkes, L., Krishna, K., Menon, A., Greenslade, G. L., & Dixon, A. R. (2008). Laparoscopic

Gill, T. S., Karantana, A., Rees, J., Pandey, S., & Dixon, A. R. (2004). Laparoscopic proctocolectomy with restorative ileal-anal pouch. *Colorectal disease* 6(6): 458-461. Gurland, B. H., & Wexner, S. D. (2002). Laparoscopic surgery for inflammatory bowel disease: results of the past decade. *Inflammatory bowel diseases* 8(1): 46-54. Hamel, C. T., Hildebrandt, U., Weiss, E. G., Feifelz, G., & Wexner, S. D. (2001). Laparoscopic surgery for inflammatory bowel disease. *Surg Endosc* 15(7): 642-645. Hashimoto, A., Funayama, Y., Naito, H., Fukushima, K., Shibata, C., Naitoh, T., Shibuya, K.,

proctocolectomy with rectal mucosectomy. *Surg Today* 31(3): 210-214. Holubar, S. D., Larson, D. W., Dozois, E. J., Pattana-Arun, J., Pemberton, J. H., & Cima, R. R.

Laparoscopic restorative proctocolectomy. *Br J Surg* 92(1): 88-93.

*and rectum* 45(2): 207-210; discussion 210-201.

Kienle, P., Z'Graggen, K., Schmidt, J., Benner, A., Weitz, J., & Buchler, M. W. (2005).

Ky, A. J., Sonoda, T., & Milsom, J. W. (2002). One-stage laparoscopic restorative

Larson, D. W., Dozois, E. J., Piotrowicz, K., Cima, R. R., Wolff, B. G., & Young-Fadok, T. M.

outcome in a case-matched series. *Dis Colon Rectum* 48(10): 1845-1850.

(2007). Laparoscopic total colectomy: an evolutionary experience. *Dis Colon Rectum*

A., & Joo, J. S. (1998). Laparoscopic colectomy for benign colorectal disease is associated with a significant reduction in disability as compared with laparotomy.

M.G., (2009). Laparoscopic vs. open total abdominal colectomy for severe colitis: impact on recovery and subsequent completion restorative proctectomy. *Dis Colon* 

J. (2000). Laparoscopic-assisted vs open colectomy for severe acute colitis in patients with inflammatory bowel disease (IBD): a retrospective study in 42

emergency and elective surgery for ulcerative colitis. *Colorectal disease* 10(4): 373-

Koyama, K., Takahashi, K., Ogawa, H., Satoh, S., Ueno, T., Kitayama, T., Matsuno, S., & Sasaki, I. (2001). Laparascope-assisted versus conventional restorative

(2009). Minimally invasive subtotal colectomy and ileal pouch-anal anastomosis for fulminant ulcerative colitis: a reasonable approach? *Dis Colon Rectum* 52(2): 187-192.

proctocolectomy: an alternative to the conventional approach? *Diseases of the colon* 

(2005). Laparoscopic-assisted vs. open ileal pouch-anal anastomosis: functional

clinically useful technique. *Dis Colon Rectum* 47(5): 753-765.

*Surgical endoscopy* 16(12): 1778-1782.

*Surg Endosc* 12(12): 1397-1400.

patients. *Surgical Endosc* 14(10): 911-914.

50(10): 1512-1519.

*Rectum* 52(1): 4-10.

378.

**6. References** 


Table 5 (continued). Perioperative data from clinical trials treating laparoscopic-assisted subtotal colectomy for severe ulcerative colitis

#### **5. Conclusion**

The earliest reports of the laparoscopic approach to ulcerative colitis in the elective setting provided little evidence of significant benefit over the standard open operative approach (Peters 1992; Wexner et al. 1992). However, with advances in technology and experience of laparoscopic surgery, more favourable results have been stated. Several studies have reported the feasibility and safety of laparoscopic assisted total colectomy for ulcerative colitis in the elective setting, and shown the advantages of laparoscopic assisted total colectomy such as reduced postoperative pain, earlier return of intestinal function, decreased length of hospital stay, and improved cosmesis (Marcello et al., 2000; Hashimoto et al., 2001; Seshadri et al., 2001; Gill et al., 2004; Kienle et al., 2005; Larson et al., 2005). On the basis of these results, several studies have evaluated the feasibility and safety of minimally invasive surgery for selected patients with severe ulcerative colitis (Dunker et al., 2000; Bell & Seymour, 2002; Marceau et al., 2007; Fowkes et al., 2008; Watanabe et al., 2009; Holubar et al., 2009; Chung et al., 2009; Maggiori et al., 2010; Telem et al., 2010). These retrospective trials indicated that minimally invasive subtotal colectomy for selected patients with severe ulcerative colitis associated with a marked reduction in wound complication rate, time to return of bowel function, and mean hospital stay, although most of these studies have reported that the mean operating time was longer than open surgery. The role of minimally invasive surgery for patients with severe ulcerative colitis is still not well defined because there is no randomized clinical trial; however, the reproducibility of the results among many institutions provides adequate evidence to demonstrate clear advantages of minimally invasive surgery for severe ulcerative colitis over a conventional open surgery. Laparoscopic assisted surgery for severe ulcerative colitis is still technically difficult because of bowel friability and hypervascularity, creating a high likelihood of perforation and bleeding. A few recent studies assessed hand-assisted laparoscopic surgery for selected patients with severe ulcerative colitis (Watanabe et al., 2009; Holubar et al., 2009; Chung et al., 2009). The use of this technique may be adequate for severe ulcerative colitis because hand-assisted surgery enables surgeons to obtain tactile sensation, manual retraction, and digital vascular control, which could allow complex laparoscopic operations to be performed more effectively and satisfactorily. Further evidence based study is needed to clarify the role of laparoscopic assisted or hand-assisted laparoscopic surgery for severe ulcerative colitis.

#### **6. References**

28 Ulcerative Colitis – Treatments, Special Populations and the Future

and progression to completion of restorative proctocolectomy.

The earliest reports of the laparoscopic approach to ulcerative colitis in the elective setting provided little evidence of significant benefit over the standard open operative approach (Peters 1992; Wexner et al. 1992). However, with advances in technology and experience of laparoscopic surgery, more favourable results have been stated. Several studies have reported the feasibility and safety of laparoscopic assisted total colectomy for ulcerative colitis in the elective setting, and shown the advantages of laparoscopic assisted total colectomy such as reduced postoperative pain, earlier return of intestinal function, decreased length of hospital stay, and improved cosmesis (Marcello et al., 2000; Hashimoto et al., 2001; Seshadri et al., 2001; Gill et al., 2004; Kienle et al., 2005; Larson et al., 2005). On the basis of these results, several studies have evaluated the feasibility and safety of minimally invasive surgery for selected patients with severe ulcerative colitis (Dunker et al., 2000; Bell & Seymour, 2002; Marceau et al., 2007; Fowkes et al., 2008; Watanabe et al., 2009; Holubar et al., 2009; Chung et al., 2009; Maggiori et al., 2010; Telem et al., 2010). These retrospective trials indicated that minimally invasive subtotal colectomy for selected patients with severe ulcerative colitis associated with a marked reduction in wound complication rate, time to return of bowel function, and mean hospital stay, although most of these studies have reported that the mean operating time was longer than open surgery. The role of minimally invasive surgery for patients with severe ulcerative colitis is still not well defined because there is no randomized clinical trial; however, the reproducibility of the results among many institutions provides adequate evidence to demonstrate clear advantages of minimally invasive surgery for severe ulcerative colitis over a conventional open surgery. Laparoscopic assisted surgery for severe ulcerative colitis is still technically difficult because of bowel friability and hypervascularity, creating a high likelihood of perforation and bleeding. A few recent studies assessed hand-assisted laparoscopic surgery for selected patients with severe ulcerative colitis (Watanabe et al., 2009; Holubar et al., 2009; Chung et al., 2009). The use of this technique may be adequate for severe ulcerative colitis because hand-assisted surgery enables surgeons to obtain tactile sensation, manual retraction, and digital vascular control, which could allow complex laparoscopic operations to be performed more effectively and satisfactorily. Further evidence based study is needed to clarify the role of laparoscopic assisted or hand-assisted laparoscopic surgery for severe

Table 5 (continued). Perioperative data from clinical trials treating laparoscopic-assisted

Technically feasible and safe. Longer operative time. Shorter hospital stay.

Safe. Associated with short-term benefits that may lead to faster recovery

(year) Conclusions

Reduced postoperative complication rate.

(2009) Technically feasible and safe. Shorter hospital stay.

subtotal colectomy for severe ulcerative colitis

Author

Watanabe (2009)

Holubar

Chung (2009)

**5. Conclusion** 

ulcerative colitis.


**3** 

*China* 

**Drug Therapy in Ulcerative Colitis** 

Xue-Gang Guo, Xiang-Ping Wang and Chang-Tai Xu

*Fourth Military Medical University, Xi'an, Shaanxi Province* 

The two primary types of inflammatory bowel disease (IBD) are ulcerative colitis (CU) and Crohn's disease (CD). These two diseases have many similarities and sometimes are difficult to distinguish from each other. However, there are several differences. UC is an inflammatory destructive disease of the large intestine characterized by motility and secretion disorders. Inflammation usually occurs in the rectum and lower part of the colon, but it may affect the entire colon. UC rarely affects the small intestine except for the end section, called the terminal ileum. UC may also be called colitis or proctitis. Inflammation makes the colon empty frequently, causing diarrhea. Ulcers formed in places where the inflammation has killed the cells of colon, bleeding ulcers and pus discharge. UC is an IBD that causes inflammation in the small intestine and colon. UC can be difficult to diagnose because its symptoms are similar to other intestinal disorders and another type of IBD called CD. CD differs from UC because it causes deeper inflammation within the intestinal wall. Also, CD usually occurs in the small intestine, although it can also occur in the mouth, esophagus, stomach, duodenum, large intestine, appendix, and anus. UC may occur in people of any age, but most often it starts between ages of 15 and 30, or less frequently between ages of 50 and 70. Children and adolescents sometimes develop the disease. UC affects men and women equally and appears to run in some families. Clinical and epidemiological data do not support a simple Mendelian model of inheritance for IBD. In its place CD and UC are considered to be complex polygenic diseases. UC is a chronic disease in which the large intestine becomes inflamed and ulcerated (pitted or eroded), leading to flare-ups (bouts or attacks) of bloody diarrhea, abdominal cramps, and fever. The long-term

The etiology is unknown for ulcerative colitis (UC). The consensus is so far that it is a response to environmental triggers (infection, drugs, or other agents) in genetically susceptible individuals. The genetic component is not as strong in UC as it is in CD. However, 10%-20% of patients with UC have at least one family member with IBD [1,2]. There are marked differences between ethnic groups with some (such as Ashkenazi Jews) having a particularly high incidence. Non-steroidal anti-inflammatory drugs may cause an episode of acute active disease in some patients with IBD. UC primarily affects young adults, but it can occur at any age from five to eighty years and women tend to be more commonly affected than men. It is a worldwide disorder with high-incidence areas that include United Kingdom, the United States, northern Europe and Australia. Low-incidence

**1. Introduction** 

risk of colon cancer is increased [1-4].

*Editorial Office of Chinese Journal of Neuroanatomy,* 

*Xijing Hospital of Digestive Disease,* 


## **Drug Therapy in Ulcerative Colitis**

Xue-Gang Guo, Xiang-Ping Wang and Chang-Tai Xu

*Xijing Hospital of Digestive Disease, Editorial Office of Chinese Journal of Neuroanatomy, Fourth Military Medical University, Xi'an, Shaanxi Province China* 

#### **1. Introduction**

30 Ulcerative Colitis – Treatments, Special Populations and the Future

Lichtiger, S., Present, D. H., Kornbluth, A., Gelernt, I., Bauer, J., Galler, G., Michelassi, F., &

Maggiori, L., Bretagnol, F., Alves, A., & Panis, Y. (2010). Laparoscopic subtotal colectomy for

Marceau, C., Alves, A., Ouaissi, M., Bouhnik, Y., Valleur, P., & Panis, Y. (2007). Laparoscopic

Nakajima, K., Lee, S. W., Cocilovo, C., Foglia, C., Kim, K., Sonoda, T., & Milsom, J. W. (2004).

Peters, W. R. (1992). Laparoscopic total proctocolectomy with creation of ileostomy for

Rivadeneira, D. E., Marcello, P. W., Roberts, P. L., Rusin, L. C., Murray, J. J., Coller, J. A., &

proctocolectomy: a comparative study. *Dis Colon Rectum* 47(8): 1371-1376. Sawada, K., Ohnishi, K., Fukui, S., Yamada, K., Yamamura, M., Amano, K., Wada, M.,

Seshadri, P. A., Poulin, E. C., Schlachta, C. M., Cadeddu, M. O., & Mamazza, J. (2001). Does

Sood, A., Midha, V., Sood, N., & Awasthi, G. (2002). A prospective, open-label trial assessing

Telem, D. A., Vine, A. J., Swain, G., Divino, C. M., Salky, B. Greenstein, A. J., Harris, M., &

Truelove, S. & Witts L. (1955). Cortisone in ulcerative colitis; final report on a therapeutic

Truelove, S. C., & Jewell D. P. (1974). Intensive intravenous regimen for severe attacks of

Watanabe, K., Funayama, Y., Fukushima, K., Shibata, C., Takahashi, K., & Sasaki, I. (2009).

Wexner, S. D., Johansen, O. B., Nogueras, J. J., & Jagelman, D. G. (1992). Laparoscopic total abdominal colectomy. A prospective trial. *Dis Colon Rectum* 35(7): 651-655.

ulcerative colitis: the time has come. *Surg Endosc* 24(7): 1616-1620.

disease: a case-matched study in 88 patients. *Surgery* 141(5): 640-644. Marcello, P. W., Milsom, J. W., Wong, S. K., Hammerhofer, K. A., Goormastic, M., Church, J.

therapy. *New Engl J Med* 330(26): 1841-1845.

*Laparosc Endosc Percutan Tech* 20(1): 27-29.

advantages? *Surg Endosc* 15(8): 837-842.

trial. *British medical journal* 2(4947): 1041-1048.

ulcerative colitis. *Lancet* 1(7866): 1067-1070.

*Dis Colon Rectum* 52(4): 640-645.

*Gastroenterol* 35(4): 328-331.

604-608.

102-105.

329.

Hanauer, S. (1994). Cyclosporine in severe ulcerative colitis refractory to steroid

acute or severe colitis with double-end ileo-sigmoidostomy in right iliac fossa. *Surg* 

subtotal colectomy for acute or severe colitis complicating inflammatory bowel

M., & Fazio, V. W. (2000). Laparoscopic restorative proctocolectomy: case-matched comparative study with open restorative proctocolectomy. *Dis Colon Rectum* 43(5):

Hand-assisted laparoscopic colorectal surgery using GelPort. *Surg Endosc* 18(1):

ulcerative colitis: report of two cases. *Journal of laparoendoscopic surgery* 2(3): 175-178.

Schoetz, D. J., Jr. (2004). Benefits of hand-assisted laparoscopic restorative

Tanida, N., & Satomi, M. (1995). Leukocytapheresis therapy, performed with leukocyte removal filter, for inflammatory bowel disease. *J Gastroenterol* 30(3): 322-

a laparoscopic approach to total abdominal colectomy and proctocolectomy offer

dexamethasone pulse therapy in moderate to severe ulcerative colitis." *J Clin* 

Katz, L. B. (2010). Laparoscopic subtotal colectomy for medically refractory

Hand-assisted laparoscopic vs. open subtotal colectomy for severe ulcerative colitis.

The two primary types of inflammatory bowel disease (IBD) are ulcerative colitis (CU) and Crohn's disease (CD). These two diseases have many similarities and sometimes are difficult to distinguish from each other. However, there are several differences. UC is an inflammatory destructive disease of the large intestine characterized by motility and secretion disorders. Inflammation usually occurs in the rectum and lower part of the colon, but it may affect the entire colon. UC rarely affects the small intestine except for the end section, called the terminal ileum. UC may also be called colitis or proctitis. Inflammation makes the colon empty frequently, causing diarrhea. Ulcers formed in places where the inflammation has killed the cells of colon, bleeding ulcers and pus discharge. UC is an IBD that causes inflammation in the small intestine and colon. UC can be difficult to diagnose because its symptoms are similar to other intestinal disorders and another type of IBD called CD. CD differs from UC because it causes deeper inflammation within the intestinal wall. Also, CD usually occurs in the small intestine, although it can also occur in the mouth, esophagus, stomach, duodenum, large intestine, appendix, and anus. UC may occur in people of any age, but most often it starts between ages of 15 and 30, or less frequently between ages of 50 and 70. Children and adolescents sometimes develop the disease. UC affects men and women equally and appears to run in some families. Clinical and epidemiological data do not support a simple Mendelian model of inheritance for IBD. In its place CD and UC are considered to be complex polygenic diseases. UC is a chronic disease in which the large intestine becomes inflamed and ulcerated (pitted or eroded), leading to flare-ups (bouts or attacks) of bloody diarrhea, abdominal cramps, and fever. The long-term risk of colon cancer is increased [1-4].

The etiology is unknown for ulcerative colitis (UC). The consensus is so far that it is a response to environmental triggers (infection, drugs, or other agents) in genetically susceptible individuals. The genetic component is not as strong in UC as it is in CD. However, 10%-20% of patients with UC have at least one family member with IBD [1,2]. There are marked differences between ethnic groups with some (such as Ashkenazi Jews) having a particularly high incidence. Non-steroidal anti-inflammatory drugs may cause an episode of acute active disease in some patients with IBD. UC primarily affects young adults, but it can occur at any age from five to eighty years and women tend to be more commonly affected than men. It is a worldwide disorder with high-incidence areas that include United Kingdom, the United States, northern Europe and Australia. Low-incidence

Drug Therapy in Ulcerative Colitis 33

the above two). Therapy for UC is aimed at quieting inflammation or relieving symptoms. It can usually control symptoms, but surgery may be required when conservative therapy fails

Both medications and surgery have been used to treat UC. However, surgery is reserved for those with severe inflammation and life-threatening complications. There is no medication so far that can cure UC. Patients with UC will typically experience periods of relapse (worsening of inflammation) followed by periods of remission lasting for months to years. During relapses, symptoms of abdominal pain, diarrhea, and rectal bleeding can worsen patients' quality of life. During remissions, these symptoms subside. Remissions usually occur because of treatment with medications or surgery, but occasionally they occur spontaneously. Since UC cannot be cured by medications, the goals of treatment with medications are to induce remissions, maintain remissions, minimize side effects of drugs, and improve the quality of life. The treatment of UC with medications is similar, though not always identical, to the treatment of CD. Medications treating UC include anti-inflammatory agents such as 5-ASA

compounds, systemic and topical corticosteroids, and immunomodulators [2, 8-10].

and comments) that reduce bowel inflammation in Table 1[2, 8-11].

that of oral and rectal formulations of mesalamine [11, 12].

Anti-inflammatory medications that decrease intestinal inflammation are analogous to arthritis medications that decrease joint inflammation (arthritis). The anti-inflammatory medications used in the treatment of UC are topical 5-ASA compounds such as sulfasalazine (Azulfidine), olsalazine (Dipentum), and mesalamine (Pentasa, Asacol, Rowasa enema) that need direct contact with the inflamed tissues in order to be effective. Systemic corticosteroids can decrease the inflammation throughout the body without direct contact with the inflamed tissue. Systemic corticosteroids have predictable side effects in long-term treatment. Immunomodulators are medications that suppress the body's immune system either by reducing the cells that are responsible for immunity, or by interfering with proteins that are important in promoting inflammation. Immunomodulators are increasingly becoming important for patients with severe UC who do not respond adequately to antiinflammatory agents. Examples of immunomodulators include 6-mercaptopurine (6-MP), azathioprine, methotrexate, and cyclosporine. There are drugs (including selected side effects

Anti-inflammatory drugs are often the first step in the treatment of UC. Sulfasalazine (Azulfidine) can be effective in reducing symptoms of ulcerative colitis, but it has a number of side effects, including nausea, vomiting, heartburn and headache. This medication can not be given if the patients are allergic to sulfa medications. To evaluate the role of multimatrix system (MMX) mesalamine in the treatment of UC, literature was obtained through searches of MEDLINE (1966-October 2007) and a bibliographic review of published articles. Key terms used in the searches included UC, mesalamine, MMX, SPD476, and Lialda. All English-language articles that were identified through the search were evaluated. The standard treatment for the induction and maintenance of remission in patients with mild-tomoderate UC is aminosalicylate products (mesalamine, sulfasalazine, balasalazide, olsalazine). Current mesalamine formulations are not ideal for long-term treatment due to issues with patient adherence secondary to complex dosing regimens and high pill burden. Clinical studies show that MMX mesalamine achieves clinical and endoscopic remission more frequently compared with placebo or mesalamine enema. Therefore, MMX mesalamine is an option in patients with UC. The cost of MMX mesalamine is comparable to

or if signs of colon cancer develop.

**2.1 Anti-inflammatory drugs** 

areas include Asia, Japan, and South America. The causes of UC remain unknown. The major theories include infection, allergy to food component, genetics, environmental factors, and immune response to bacteria or other antigens [1]. Typical symptoms during flare-ups include abdominal cramps, an urge to move the bowels, and diarrhea (typically bloody). The diagnosis is based on an examination of the sigmoid colon using a flexible viewing tube (sigmoidoscopy) or an examination of the large intestine using a flexible viewing tube (colonoscopy). People who have had UC for a long time may develop colon cancer. Treatment is aimed at controlling the inflammation, reducing symptoms, and replacing any lost fluids and nutrients. UC may start at any age but usually begins between the ages of 15 and 30. A small group of people have their first attack between the ages of 50 and 70. UC usually does not affect the full thickness of the wall of the large intestine and hardly ever affects the small intestine. The disease usually begins in the rectum or the rectum and the sigmoid colon (the lower end of the large intestine) but may eventually spread along part or all of the large intestine. UC, which is confined to the rectum, is a very common and relatively benign form of UC. In some people, most of the large intestine is affected early on. Ulcerative colitis (UC) affects about one in 1000 people in the Western world. Peak incidence is between the ages of 10 and 40 years. UC may affect people of any age and 15% of people are over the age of 60 at diagnosis [1-4]. The incidence of UC in North America is 10-12 cases per 100,000, with a peak incidence of UC occurring between the ages of 15 and 25. There is thought to be a bimodal distribution in age of onset, with a second peak in incidence occurring in the 6th decade of life. The disease affects females more than males with highest incidences in the United States, Canada, the United Kingdom, and Scandinavia. Higher incidences are seen in northern locations compared to southern locations in Europe and the United States. Epidemiologic data support genetic contribution to the pathogenesis of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD [5]: TNF-308A, CARD15 (NOD2), MIF-173 gene, N-acetyltransferase 2 (NAT2), NKG2D (natural killer cell 2D), STAT6 (signal transducer and activator of transcription 6), CTLA-4 (cytotoxic T lymphocyte antigen-4), MICA-MICB (major histocompatibility complex A and B), HLA-DRB1 gene, HLA class-II gene, IL-18 gene (interleukin-18 gene), IL-4 gene, MICA-A5, CD14 gene, TLR4 gene, Fas-670 gene, p53 gene and NF-kappaB. The characterization of these novel genes is potential to identify therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD (UC and CD). The diagnosis of UC is made from the patient's medical history, a stool examination, sigmoidoscopy findings, and biopsy of specimens from the rectum or colon.

#### **2. Drug treatment**

The goals of treatment of UC are to induce and maintain remission of symptoms and inflammation of the inner lining of colon [2, 4, 6, 7]. Treatment options are determined according to the extent of the inflammation and the severity of the disease. Some people have long periods of remission, which can last for years. Unfortunately, the disease usually recurs periodically during an individual's lifetime. Predicting when a flare-up may occur is not possible, but early recognition of symptoms results in a better response to treatment. Patients with this disease are divided into three groups based on the site of involvement, which is important for treatment and prognosis. (1) Proctitis (involving the rectum, the last part of the colon near the anus); (2) Left-sided colitis (from the rectum to the splenic flexure — the area below the ribs on the left side); (3) Pancolitis (involvement more extensive than

areas include Asia, Japan, and South America. The causes of UC remain unknown. The major theories include infection, allergy to food component, genetics, environmental factors, and immune response to bacteria or other antigens [1]. Typical symptoms during flare-ups include abdominal cramps, an urge to move the bowels, and diarrhea (typically bloody). The diagnosis is based on an examination of the sigmoid colon using a flexible viewing tube (sigmoidoscopy) or an examination of the large intestine using a flexible viewing tube (colonoscopy). People who have had UC for a long time may develop colon cancer. Treatment is aimed at controlling the inflammation, reducing symptoms, and replacing any lost fluids and nutrients. UC may start at any age but usually begins between the ages of 15 and 30. A small group of people have their first attack between the ages of 50 and 70. UC usually does not affect the full thickness of the wall of the large intestine and hardly ever affects the small intestine. The disease usually begins in the rectum or the rectum and the sigmoid colon (the lower end of the large intestine) but may eventually spread along part or all of the large intestine. UC, which is confined to the rectum, is a very common and relatively benign form of UC. In some people, most of the large intestine is affected early on. Ulcerative colitis (UC) affects about one in 1000 people in the Western world. Peak incidence is between the ages of 10 and 40 years. UC may affect people of any age and 15% of people are over the age of 60 at diagnosis [1-4]. The incidence of UC in North America is 10-12 cases per 100,000, with a peak incidence of UC occurring between the ages of 15 and 25. There is thought to be a bimodal distribution in age of onset, with a second peak in incidence occurring in the 6th decade of life. The disease affects females more than males with highest incidences in the United States, Canada, the United Kingdom, and Scandinavia. Higher incidences are seen in northern locations compared to southern locations in Europe and the United States. Epidemiologic data support genetic contribution to the pathogenesis of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD [5]: TNF-308A, CARD15 (NOD2), MIF-173 gene, N-acetyltransferase 2 (NAT2), NKG2D (natural killer cell 2D), STAT6 (signal transducer and activator of transcription 6), CTLA-4 (cytotoxic T lymphocyte antigen-4), MICA-MICB (major histocompatibility complex A and B), HLA-DRB1 gene, HLA class-II gene, IL-18 gene (interleukin-18 gene), IL-4 gene, MICA-A5, CD14 gene, TLR4 gene, Fas-670 gene, p53 gene and NF-kappaB. The characterization of these novel genes is potential to identify therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD (UC and CD). The diagnosis of UC is made from the patient's medical history, a stool examination, sigmoidoscopy findings, and biopsy

The goals of treatment of UC are to induce and maintain remission of symptoms and inflammation of the inner lining of colon [2, 4, 6, 7]. Treatment options are determined according to the extent of the inflammation and the severity of the disease. Some people have long periods of remission, which can last for years. Unfortunately, the disease usually recurs periodically during an individual's lifetime. Predicting when a flare-up may occur is not possible, but early recognition of symptoms results in a better response to treatment. Patients with this disease are divided into three groups based on the site of involvement, which is important for treatment and prognosis. (1) Proctitis (involving the rectum, the last part of the colon near the anus); (2) Left-sided colitis (from the rectum to the splenic flexure — the area below the ribs on the left side); (3) Pancolitis (involvement more extensive than

of specimens from the rectum or colon.

**2. Drug treatment** 

the above two). Therapy for UC is aimed at quieting inflammation or relieving symptoms. It can usually control symptoms, but surgery may be required when conservative therapy fails or if signs of colon cancer develop.

Both medications and surgery have been used to treat UC. However, surgery is reserved for those with severe inflammation and life-threatening complications. There is no medication so far that can cure UC. Patients with UC will typically experience periods of relapse (worsening of inflammation) followed by periods of remission lasting for months to years. During relapses, symptoms of abdominal pain, diarrhea, and rectal bleeding can worsen patients' quality of life. During remissions, these symptoms subside. Remissions usually occur because of treatment with medications or surgery, but occasionally they occur spontaneously. Since UC cannot be cured by medications, the goals of treatment with medications are to induce remissions, maintain remissions, minimize side effects of drugs, and improve the quality of life. The treatment of UC with medications is similar, though not always identical, to the treatment of CD. Medications treating UC include anti-inflammatory agents such as 5-ASA compounds, systemic and topical corticosteroids, and immunomodulators [2, 8-10].

Anti-inflammatory medications that decrease intestinal inflammation are analogous to arthritis medications that decrease joint inflammation (arthritis). The anti-inflammatory medications used in the treatment of UC are topical 5-ASA compounds such as sulfasalazine (Azulfidine), olsalazine (Dipentum), and mesalamine (Pentasa, Asacol, Rowasa enema) that need direct contact with the inflamed tissues in order to be effective. Systemic corticosteroids can decrease the inflammation throughout the body without direct contact with the inflamed tissue. Systemic corticosteroids have predictable side effects in long-term treatment. Immunomodulators are medications that suppress the body's immune system either by reducing the cells that are responsible for immunity, or by interfering with proteins that are important in promoting inflammation. Immunomodulators are increasingly becoming important for patients with severe UC who do not respond adequately to antiinflammatory agents. Examples of immunomodulators include 6-mercaptopurine (6-MP), azathioprine, methotrexate, and cyclosporine. There are drugs (including selected side effects and comments) that reduce bowel inflammation in Table 1[2, 8-11].

#### **2.1 Anti-inflammatory drugs**

Anti-inflammatory drugs are often the first step in the treatment of UC. Sulfasalazine (Azulfidine) can be effective in reducing symptoms of ulcerative colitis, but it has a number of side effects, including nausea, vomiting, heartburn and headache. This medication can not be given if the patients are allergic to sulfa medications. To evaluate the role of multimatrix system (MMX) mesalamine in the treatment of UC, literature was obtained through searches of MEDLINE (1966-October 2007) and a bibliographic review of published articles. Key terms used in the searches included UC, mesalamine, MMX, SPD476, and Lialda. All English-language articles that were identified through the search were evaluated. The standard treatment for the induction and maintenance of remission in patients with mild-tomoderate UC is aminosalicylate products (mesalamine, sulfasalazine, balasalazide, olsalazine). Current mesalamine formulations are not ideal for long-term treatment due to issues with patient adherence secondary to complex dosing regimens and high pill burden. Clinical studies show that MMX mesalamine achieves clinical and endoscopic remission more frequently compared with placebo or mesalamine enema. Therefore, MMX mesalamine is an option in patients with UC. The cost of MMX mesalamine is comparable to that of oral and rectal formulations of mesalamine [11, 12].

Drug Therapy in Ulcerative Colitis 35

Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a To systematically evaluate the efficacy of antibacterial therapy in ulcerative colitis, Rahimi et al [15] carried out a meta analysis of controlled clinical trials. Within the time period 1966 through September 2006, PUBMED, EMBASE, and SCOPUS were searched for clinical trial studies that investigated the efficacy of antibiotics in ulcerative colitis. These results suggest that adjunctive antibacterial therapy is effective for induction of clinical remission in UC. Mesalamine is used to treat ulcerative colitis (a condition in which part or all of the lining of the colon [large intestine] is swollen or worn away). Mesalamine delayed-release tablets and controlled-release capsules may be used to treat ulcerative colitis that affects any part of the colon. Mesalamine suppositories and enemas should only be used to treat inflammation of the lower part of the colon. Mesalamine is in a class of medications called anti-inflammatory agents. It works by stopping the body from producing a certain substance that may cause pain or inflammation. Mesalamine (Asacol, Rowasa) and olsalazine (Dipentum) tend to have fewer side effects than sulfasalazine has. The patients with UC take them in tablet form or use them rectally in the form of enemas or suppositories, depending on the area of the colon affected by ulcerative colitis. Mesalamine enemas can relieve signs and symptoms in more than 80 percent of people with ulcerative colitis in the lower left side of their colon and

rectum. Olsalazine may cause or worsen existing diarrhea in some people [2-4].

Balsalazide is more effective than mesalazine in induction of remission, but balsalazide has no benefit compared with mesalazine in preventing relapse in the population selected. The number of patients with any adverse events and withdrawals because of severe adverse

Articles cited were identified *via* a PubMed search, utilizing the words IBD, adherence, compliance, medication and UC. Medication non-adherence is multifactorial involving factors other than dosing frequency. Male gender (OR: 2.06), new patient status (OR: 2.14), work and travel pressures (OR: 4.9) and shorter disease duration (OR: 2.1), among others are

Infusion reactions are potential immediate side effects that occur during the infusion such as fever, chills, hives, decreased blood pressure, or difficulty

Patients should be screened for tuberculosis before initiating treatment.

Side effect are similar to infliximab except does not cause infusion reactions. Hypersensitive reactions include rash, urticaria, pruritis, and hives.

breathing.

**Drugs Selected Side Effects Comments** 

abdominal pain, liver dysfunction, low

Infliximab Infusion reactions, infections, cancer,

Adalimumab Pain or itching at the injection site,

Table 1. Drugs selected side effects for therapy UC

events is similar for mesalazine and balsalazide [16].

headache, infections, cancer, and hypersensitivity reactions.

white blood cell count.


Abdominal pain, dizziness, and fatigue are related to dose; hepatitis and

pancreatitis are unrelated to

Most side effects seen with sulfasalazine may occur with

aminosalicylates but much

Diabetes and high blood pressure are more likely to occur in people who have

any of the other

less frequently.

other risk factors.

Same side effects as prednisone but to a lesser

liver dysfunction

required.

dependent

women.

Side effects that are usually dose dependent include bone marrow suppression and

Interval blood monitoring is

Side effects become more likely with long-term use.

Liver toxicity is likely dose

Not prescribed for pregnant

degree.

dose.

**Drugs Selected Side Effects Comments** 

Sulfasalazine Common: Nausea, headache, dizziness,

Common: Fever, rash.

Prednisone Diabetes mellitus, high blood pressure,

Budesonide Diabetes mellitus, high blood pressure,

Cyclosporine High blood pressure, nausea, vomiting,

lymphatic system).

pregnancy.

Methotrexate Nausea, vomiting, abdominal distress,

diarrhea, kidney failure, tremors, infections, seizures, neuropathy,

development of lymphomas (cancers of the

headache, rash, soreness of the mouth, fatigue, scarring of the liver (cirrhosis), low

Causes abortions and birth defects during

white blood cell count, infections.

density).

gastritis, peptic ulcer disease.

infertility.

fatigue, fever, rash, reversible male

(pneumonitis); hemolytic anemia.

For olsalazine: Watery diarrhea.

Uncommon: Inflammation of the liver (hepatitis), pancreas (pancreatitis), or lung

Uncommon: Pancreatitis, inflammation of the pericardium (pericarditis), pneumonitis

cataracts, osteoporosis, thinning of skin, mental problems, acute psychosis, mood swings, infections, acne, excessive body hair (hirsutism), menstrual irregularities,

cataracts, osteoporosis (decreased bone

Anorexia, nausea, vomiting, infection, cancer, allergic reactions, pancreatitis, low white blood cell count, bone marrow suppression, liver dysfunction.

**Aminosalicylates**

Balsalazide Mesalamine Olsalazine

**Corticosteroids**

**Immunomodulators**

Azathioprine Mercaptopurine


Table 1. Drugs selected side effects for therapy UC

Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a To systematically evaluate the efficacy of antibacterial therapy in ulcerative colitis, Rahimi et al [15] carried out a meta analysis of controlled clinical trials. Within the time period 1966 through September 2006, PUBMED, EMBASE, and SCOPUS were searched for clinical trial studies that investigated the efficacy of antibiotics in ulcerative colitis. These results suggest that adjunctive antibacterial therapy is effective for induction of clinical remission in UC. Mesalamine is used to treat ulcerative colitis (a condition in which part or all of the lining of the colon [large intestine] is swollen or worn away). Mesalamine delayed-release tablets and controlled-release capsules may be used to treat ulcerative colitis that affects any part of the colon. Mesalamine suppositories and enemas should only be used to treat inflammation of the lower part of the colon. Mesalamine is in a class of medications called anti-inflammatory agents. It works by stopping the body from producing a certain substance that may cause pain or inflammation. Mesalamine (Asacol, Rowasa) and olsalazine (Dipentum) tend to have fewer side effects than sulfasalazine has. The patients with UC take them in tablet form or use them rectally in the form of enemas or suppositories, depending on the area of the colon affected by ulcerative colitis. Mesalamine enemas can relieve signs and symptoms in more than 80 percent of people with ulcerative colitis in the lower left side of their colon and rectum. Olsalazine may cause or worsen existing diarrhea in some people [2-4].

Balsalazide is more effective than mesalazine in induction of remission, but balsalazide has no benefit compared with mesalazine in preventing relapse in the population selected. The number of patients with any adverse events and withdrawals because of severe adverse events is similar for mesalazine and balsalazide [16].

Articles cited were identified *via* a PubMed search, utilizing the words IBD, adherence, compliance, medication and UC. Medication non-adherence is multifactorial involving factors other than dosing frequency. Male gender (OR: 2.06), new patient status (OR: 2.14), work and travel pressures (OR: 4.9) and shorter disease duration (OR: 2.1), among others are

Drug Therapy in Ulcerative Colitis 37

has a favorable safety profile. With the advantage of low pill burden and easy dosing schedule,

The efficacy of 5-ASAs in ulcerative colitis (UC) has been studied previously in metaanalyses. However, several randomized controlled trials (RCTs) have been published recently, and no previous meta-analysis has studied the effect of 5-ASA dosage used. Ford *et al* [23] suggested that 5-ASAs are highly effective for inducing remission and preventing relapse in UC. Evidence suggests that 5-ASA doses of ≥2.0 g/day have greater efficacy,

Sulfasalazine (SSZ) does not differ from mesalamine or olsalazine in terms of efficacy and tolerability in UC. Withdrawal from study due to adverse events was significantly lower for balsalazide compared with SSZ. Convincing conclusions on the comparison of effectiveness and safety of balsalazide and SSZ in UC remains to be elucidated by further clinical trials. Considering the lower cost of treatment with SSZ and the equal rate of adverse events with other 5-ASAa, it is not surprising to suggest SSZ as a first-choice treatment for UC and

Ulcerative proctitis (UP) is a common presentation of UC. Extensive Medline/Embase literature search was performed to identify relevant articles. Topical medication with rectally administered 5-ASA/corticosteroid suppositories or enemas is an effective treatment for most UP patients. Locally administered 5-ASA is more efficacious than oral compounds. The combination of topical 5-ASA and oral 5-ASA or topical steroids should be considered for escalation of treatment. Maintenance treatment is indicated in all UC cases. 5- ASA suppositories are suggested as first-line maintenance therapy if accepted by patients, although oral 5-ASA as maintenance therapy might prevent proximal extension of the disease. After re-assessment, chronically active patients refractory or intolerant to 5-ASAs and corticosteroids may require immunomodulators or biological therapy [12, 20-23]. Rectal 5-ASA should be considered a first-line therapy for patients with mild to moderately active distal UC. The optimal total daily dose and dose frequency of 5-ASA remain to be determined. Future research should define differences in efficacy among patient subgroups defined by proximal disease margin and disease activity. There is a strong need for consensus

standardization of outcome measurements for clinical trials in ulcerative colitis [25]..

Infliximab is effective for treatment of moderate-to-severe UC and is recommended for patients who have had an inadequate response to medical therapy or who are intolerant of or do not desire to take the potential risk of using specific agents including immunomodulators (cyclosporine A, azathioprine, or 6-mercaptopurine), corticosteroids, and, potentially, mesalamine. Future trials are needed to assess the efficacy of infliximab with immunomodulators to see if additional benefit is achieved so that the risk-benefit ratio is positive. Based on the favorable efficacy of infliximab for UC therapy, the ground work has been established for evaluating infliximab and addressing some of the many unanswered questions and also for assessing other anti-TNF agents and streamlining the anti-TNG antibody to improve efficacy, reduce side effects, and ease administration [22]. Infliximab (Remicade) is specifically for adults and children with moderate to severe ulcerative colitis who don't respond to or can't tolerate other treatments. The drug has been linked to an increased risk of infection, especially tuberculosis, and may increase your risk of blood problems and cancer. Before taking infliximab a skin test for tuberculosis and a chest X-ray are necessary if the patients lived or traveled extensively where tuberculosis has been found. Also, because Remicade contains mouse protein, it can cause serious allergic reactions in some people — reactions that may be delayed for days to weeks after starting

it may potentially improve patient compliance and treatment success [20].

although doses >2.5 g/day do not appear to lead to higher remission rates.

reserve 5-ASAs for when SSZ intolerability occurs [24].

proven predictors of non-adherence in UC. These indicators can identify 'at-risk' patients and allow an individually tailored treatment approach to be introduced that optimizes medication adherence. A collaborative relationship between physician and patient is important. Several strategies for improving adherence have been proven effective including open dialogue that consideration the patient's health beliefs and concerns, providing educational (e.g. verbal/written information, self-management programmes) and behavioural interventions (e.g. calendar blister packs, cues/reminders). Hawthorne *et al* [17] considered that educational and behavioural interventions tailored to individual patients can optimize medication adherence. Additional studies combining educational and behavioural interventions may provide further strategies for improving medication adherence rates in UC. Swaminath *et al* [18]reviews current data to optimize the use of both older and newer drugs in inflammatory bowel disease. For patients with severe UC, steroid dosing has been clarified, and a mega-analysis of steroid outcomes and toxicities has been reported. In regard to mesalamine, recent information has suggested benefit of a higher dose of pH-dependent release mesalamine for patients with moderate UC. Also, a once-daily formulation with multi-matrix system (MMX) technology (Shire Pharmaceuticals, Wayne, PA), has been approved. In regard to cyclosporine, two centers have reported an increased rate of colectomy over a long-duration follow-up of a cyclosporine course given for UC. Additional information regarding thiopurines has been published, including the use of metabolite testing and duration of therapy for these drugs [19, 20].

5-aminosalicylic acids (5-ASAs), a number of oral 5-ASA agents are commercially available, including azo-bond pro-drugs such as sulfasalazine, olsalazine and balsalazide, and delayed- and controlled-release forms of mesalazine [12, 21, 22]. The effectiveness of oral therapy relies on good compliance, which may be adversely affected by frequent daily dosing and a large number of tablets. Furthermore, poor adherence has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine including the unique multi-matrix delivery system and mesalazine granules were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. The advantage of low pill burden may contribute to increased long-term compliance and treatment success in clinical practice and might potentially further contribute to a decline in the risk for UC-associated colon cancers. In this systematic review, Lakatos *et al* [19] summarized the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.

5-ASA agents are the first-line therapy for UC. A high-dose, once-daily formulation of 5- ASA known as MMX mesalamine has recently been approved for the treatment of UC. A systematic review of published literature was performed on PubMed using the search terms 'MMX mesalamine' and 'Lialda'. Abstracts presented at US gastroenterology conferences between 2006 and 2007, were also reviewed. MMX mesalamine uses a novel multi-matrix delivery system to achieve a sustained release of 5-ASA throughout the colon. Clinical trials have demonstrated that MMX mesalamine 2.4 g/day or 4.8 g/day is superior to placebo in inducing remission in active mild to moderate UC. The drug is well tolerated with a safety profile comparable to other oral 5-ASAs agents. With a high-dose formulation of 1.2 g 5-ASA per tablet, MMX mesalamine can be administered conveniently at two to four pills once a day. MMX mesalamine is the first and only approved once-daily 5-ASAs treatment option for patients with UC. It is efficacious for the induction of remission in mild to moderate UC and

proven predictors of non-adherence in UC. These indicators can identify 'at-risk' patients and allow an individually tailored treatment approach to be introduced that optimizes medication adherence. A collaborative relationship between physician and patient is important. Several strategies for improving adherence have been proven effective including open dialogue that consideration the patient's health beliefs and concerns, providing educational (e.g. verbal/written information, self-management programmes) and behavioural interventions (e.g. calendar blister packs, cues/reminders). Hawthorne *et al* [17] considered that educational and behavioural interventions tailored to individual patients can optimize medication adherence. Additional studies combining educational and behavioural interventions may provide further strategies for improving medication adherence rates in UC. Swaminath *et al* [18]reviews current data to optimize the use of both older and newer drugs in inflammatory bowel disease. For patients with severe UC, steroid dosing has been clarified, and a mega-analysis of steroid outcomes and toxicities has been reported. In regard to mesalamine, recent information has suggested benefit of a higher dose of pH-dependent release mesalamine for patients with moderate UC. Also, a once-daily formulation with multi-matrix system (MMX) technology (Shire Pharmaceuticals, Wayne, PA), has been approved. In regard to cyclosporine, two centers have reported an increased rate of colectomy over a long-duration follow-up of a cyclosporine course given for UC. Additional information regarding thiopurines has been published, including the use of

5-aminosalicylic acids (5-ASAs), a number of oral 5-ASA agents are commercially available, including azo-bond pro-drugs such as sulfasalazine, olsalazine and balsalazide, and delayed- and controlled-release forms of mesalazine [12, 21, 22]. The effectiveness of oral therapy relies on good compliance, which may be adversely affected by frequent daily dosing and a large number of tablets. Furthermore, poor adherence has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine including the unique multi-matrix delivery system and mesalazine granules were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. The advantage of low pill burden may contribute to increased long-term compliance and treatment success in clinical practice and might potentially further contribute to a decline in the risk for UC-associated colon cancers. In this systematic review, Lakatos *et al* [19] summarized the available literature on the short- and medium-term

5-ASA agents are the first-line therapy for UC. A high-dose, once-daily formulation of 5- ASA known as MMX mesalamine has recently been approved for the treatment of UC. A systematic review of published literature was performed on PubMed using the search terms 'MMX mesalamine' and 'Lialda'. Abstracts presented at US gastroenterology conferences between 2006 and 2007, were also reviewed. MMX mesalamine uses a novel multi-matrix delivery system to achieve a sustained release of 5-ASA throughout the colon. Clinical trials have demonstrated that MMX mesalamine 2.4 g/day or 4.8 g/day is superior to placebo in inducing remission in active mild to moderate UC. The drug is well tolerated with a safety profile comparable to other oral 5-ASAs agents. With a high-dose formulation of 1.2 g 5-ASA per tablet, MMX mesalamine can be administered conveniently at two to four pills once a day. MMX mesalamine is the first and only approved once-daily 5-ASAs treatment option for patients with UC. It is efficacious for the induction of remission in mild to moderate UC and

metabolite testing and duration of therapy for these drugs [19, 20].

efficacy and safety of the new once-daily mesalazine formulations.

has a favorable safety profile. With the advantage of low pill burden and easy dosing schedule, it may potentially improve patient compliance and treatment success [20].

The efficacy of 5-ASAs in ulcerative colitis (UC) has been studied previously in metaanalyses. However, several randomized controlled trials (RCTs) have been published recently, and no previous meta-analysis has studied the effect of 5-ASA dosage used. Ford *et al* [23] suggested that 5-ASAs are highly effective for inducing remission and preventing relapse in UC. Evidence suggests that 5-ASA doses of ≥2.0 g/day have greater efficacy, although doses >2.5 g/day do not appear to lead to higher remission rates.

Sulfasalazine (SSZ) does not differ from mesalamine or olsalazine in terms of efficacy and tolerability in UC. Withdrawal from study due to adverse events was significantly lower for balsalazide compared with SSZ. Convincing conclusions on the comparison of effectiveness and safety of balsalazide and SSZ in UC remains to be elucidated by further clinical trials. Considering the lower cost of treatment with SSZ and the equal rate of adverse events with other 5-ASAa, it is not surprising to suggest SSZ as a first-choice treatment for UC and reserve 5-ASAs for when SSZ intolerability occurs [24].

Ulcerative proctitis (UP) is a common presentation of UC. Extensive Medline/Embase literature search was performed to identify relevant articles. Topical medication with rectally administered 5-ASA/corticosteroid suppositories or enemas is an effective treatment for most UP patients. Locally administered 5-ASA is more efficacious than oral compounds. The combination of topical 5-ASA and oral 5-ASA or topical steroids should be considered for escalation of treatment. Maintenance treatment is indicated in all UC cases. 5- ASA suppositories are suggested as first-line maintenance therapy if accepted by patients, although oral 5-ASA as maintenance therapy might prevent proximal extension of the disease. After re-assessment, chronically active patients refractory or intolerant to 5-ASAs and corticosteroids may require immunomodulators or biological therapy [12, 20-23]. Rectal 5-ASA should be considered a first-line therapy for patients with mild to moderately active distal UC. The optimal total daily dose and dose frequency of 5-ASA remain to be determined. Future research should define differences in efficacy among patient subgroups defined by proximal disease margin and disease activity. There is a strong need for consensus standardization of outcome measurements for clinical trials in ulcerative colitis [25]..

Infliximab is effective for treatment of moderate-to-severe UC and is recommended for patients who have had an inadequate response to medical therapy or who are intolerant of or do not desire to take the potential risk of using specific agents including immunomodulators (cyclosporine A, azathioprine, or 6-mercaptopurine), corticosteroids, and, potentially, mesalamine. Future trials are needed to assess the efficacy of infliximab with immunomodulators to see if additional benefit is achieved so that the risk-benefit ratio is positive. Based on the favorable efficacy of infliximab for UC therapy, the ground work has been established for evaluating infliximab and addressing some of the many unanswered questions and also for assessing other anti-TNF agents and streamlining the anti-TNG antibody to improve efficacy, reduce side effects, and ease administration [22]. Infliximab (Remicade) is specifically for adults and children with moderate to severe ulcerative colitis who don't respond to or can't tolerate other treatments. The drug has been linked to an increased risk of infection, especially tuberculosis, and may increase your risk of blood problems and cancer. Before taking infliximab a skin test for tuberculosis and a chest X-ray are necessary if the patients lived or traveled extensively where tuberculosis has been found. Also, because Remicade contains mouse protein, it can cause serious allergic reactions in some people — reactions that may be delayed for days to weeks after starting

Drug Therapy in Ulcerative Colitis 39

Cyclosporine (Neoral, Sandimmune), a potent drug, is normally reserved for people who

Published trials evaluating the efficacy of 6-thioguanine anti-metabolites in the treatment of UC have yielded conflicting results. Leung *et al* [30] performed a systematic review and meta-analysis to evaluate the clinical efficacy of 6-thioguanine anti-metabolites for the maintenance of clinical remission after standard induction with corticosteroids. A comprehensive search of online databases was conducted. Only randomized controlled trials with 6-thioguanine antimetabolites within a minimum duration of follow-up of 6 months were selected. Five trials were included in the meta-analysis. Pooled results demonstrated a modest efficacy of azathioprine (AZA) for the treatment of ulcerative colitis. However, the use of AZA for the management of UC is not based on high-quality evidence. There remains controversy regarding the efficacy of thiopurine analogs (AZA and 6-MP), methotrexate (MTX), and cyclosporine for the treatment of inflammatory bowel disease (IBD). An updated systematic review of the literature to clarify the efficacy of immunosuppressive therapy at inducing remission and preventing relapse in UC and CD was performed. Most evidence relates to AZA/6-MP where there is no statistically significant benefit at inducing remission in active CD and UC. Thiopurine analogs may prevent relapse in quiescent UC and CD. However, there is a paucity of data for

Over the last decade, the increasing knowledge on the pathogenic mechanisms underlying intestinal inflammation has led to the development of a number of biological agents, mainly addressed to molecules and/or pathways demonstrated to have a pathogenic role in UC. In UC, clinical course and therapeutic decisions mainly depend on disease activity and extent. While therapeutic approach to mild-to-moderate UC by using aminosalicylates and corticosteroids has been well established, treatment of severe UC is far from being satisfactory. A severe attack of UC remains a challenge to be managed jointly by gastroenterology, surgery, and intensive care units. However, the recent introduction of biological therapies has led to promising changes in the management of UC patients. Aim of this paper is to review the recent advances and future perspectives for the use of biological agents in UC [32, 33]. Side effects of cyclosporine include high blood pressure, renal function impairment, and tingling sensations in the extremities. More serous side effects

Mucosal macrophages play an important role in the mucosal immune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major contributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development,

Progress has occurred in all major areas relevant to IBD pathogenesis, which include the external environment, genetics, microbial factors, and the immune system. This review presents an update on the specific major advances that have occurred in each of these four areas, briefly discusses the therapeutic implications of the observed progress, and points out the additional work that needs to be accomplished in the next few years to reach a full

don't respond well to other medications or who face surgery because of severe UC.

immunosuppressive therapy in IBD and more research is needed [31].

recurrence and exacerbation of the inflammatory process in IBD [34-36].

include anaphylactic shock and seizures.

understanding of IBD etiopathogenesis [35,36].

treatment. Once started, infliximab is often continued as long-term therapy, although its effectiveness may wear off over time.

#### **2.2 Corticosteroids**

Corticosteroids can help reduce inflammation, but they have numerous side effects, including a puffy face, excessive facial hair, night sweats, insomnia and hyperactivity. Longterm use of these drugs in children can lead to stunted growth. Also, corticosteroids don't work for everyone who has ulcerative colitis. Doctors generally use corticosteroids only if you have moderate to severe inflammatory bowel disease that doesn't respond to other treatments. Corticosteroids aren't for long-term use and are generally prescribed for a period of three to four months. They may also be used in conjunction with other medications as a means to induce remission. These, too, are only for short-term use [2, 8].

MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through December 2010) by Ford *et al* [26]. Randomized controlled trials (RCTs) recruiting adults with active or quiescent CD comparing standard glucocorticosteroids or budesonide with placebo or each other, or comparing standard glucocorticosteroids with placebo in active UC, were eligible. Dichotomous data were extracted to obtain relative risk (RR) of failure to achieve remission in active disease, and RR of relapse of activity in quiescent disease, with a 95% confidence interval (CI). Adverse events data were extracted where reported. Standard glucocorticosteroids are probably effective in inducing remission in UC, and may be of benefit in CD. Budesonide induces remission in active CD, but is less effective than standard glucocorticosteroids, and is of no benefit in preventing CD relapse.

Recent progress in both basic and clinical research has led us to develop sophisticated and effective medical therapy of UC. Although classical agents such as aminosalicylates, corticosteroids and immunomodulatory drugs have remained as the gold standard for decades, their novel formulations and/or dosage regimens have changed their placements in the medical management of UC. In addition, studies have shown that a number of novel therapeutic agents, designed to target specific mechanisms involved in the inflammatory cascade, have efficacy for the treatment of UC and they will have significant clinical impacts in the near future. A clear understanding of the proven and potential benefits of both the standard and emerging therapies will be required for the optimum individual care of patients with varied clinical presentations [12, 18, 27-29].

#### **2.3 Immune system suppressors**

These drugs also reduce inflammation, but they target the immune system rather than inflammation itself. Because immune suppressors can be effective in treating ulcerative colitis, scientists theorize that damage of the digestive tissues is caused by the body's immune response to an invading virus or bacterium or even to patients own tissue. By suppressing this response, inflammation is also reduced. Azathioprine (Imuran) and mercaptopurine (Purinethol) have been used to treat CD and UC for years, but their role in ulcerative colitis is only now being studied. Because azathioprine and mercaptopurine act slowly, they're sometimes initially combined with a corticosteroid, but in time, they seem to produce benefits on their own, with less long-term toxicity. Side effects can include allergic reactions, bone marrow suppression, infections, and inflammation of the liver and pancreas. If a patient is taking either of these medications, he or she'll need to follow up closely with his or her doctor and have your blood checked regularly to look for side effects.

treatment. Once started, infliximab is often continued as long-term therapy, although its

Corticosteroids can help reduce inflammation, but they have numerous side effects, including a puffy face, excessive facial hair, night sweats, insomnia and hyperactivity. Longterm use of these drugs in children can lead to stunted growth. Also, corticosteroids don't work for everyone who has ulcerative colitis. Doctors generally use corticosteroids only if you have moderate to severe inflammatory bowel disease that doesn't respond to other treatments. Corticosteroids aren't for long-term use and are generally prescribed for a period of three to four months. They may also be used in conjunction with other medications as a

MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through December 2010) by Ford *et al* [26]. Randomized controlled trials (RCTs) recruiting adults with active or quiescent CD comparing standard glucocorticosteroids or budesonide with placebo or each other, or comparing standard glucocorticosteroids with placebo in active UC, were eligible. Dichotomous data were extracted to obtain relative risk (RR) of failure to achieve remission in active disease, and RR of relapse of activity in quiescent disease, with a 95% confidence interval (CI). Adverse events data were extracted where reported. Standard glucocorticosteroids are probably effective in inducing remission in UC, and may be of benefit in CD. Budesonide induces remission in active CD, but is less effective

Recent progress in both basic and clinical research has led us to develop sophisticated and effective medical therapy of UC. Although classical agents such as aminosalicylates, corticosteroids and immunomodulatory drugs have remained as the gold standard for decades, their novel formulations and/or dosage regimens have changed their placements in the medical management of UC. In addition, studies have shown that a number of novel therapeutic agents, designed to target specific mechanisms involved in the inflammatory cascade, have efficacy for the treatment of UC and they will have significant clinical impacts in the near future. A clear understanding of the proven and potential benefits of both the standard and emerging therapies will be required for the optimum individual care of

These drugs also reduce inflammation, but they target the immune system rather than inflammation itself. Because immune suppressors can be effective in treating ulcerative colitis, scientists theorize that damage of the digestive tissues is caused by the body's immune response to an invading virus or bacterium or even to patients own tissue. By suppressing this response, inflammation is also reduced. Azathioprine (Imuran) and mercaptopurine (Purinethol) have been used to treat CD and UC for years, but their role in ulcerative colitis is only now being studied. Because azathioprine and mercaptopurine act slowly, they're sometimes initially combined with a corticosteroid, but in time, they seem to produce benefits on their own, with less long-term toxicity. Side effects can include allergic reactions, bone marrow suppression, infections, and inflammation of the liver and pancreas. If a patient is taking either of these medications, he or she'll need to follow up closely with his or her doctor and have your blood checked regularly to look for side effects.

means to induce remission. These, too, are only for short-term use [2, 8].

than standard glucocorticosteroids, and is of no benefit in preventing CD relapse.

patients with varied clinical presentations [12, 18, 27-29].

**2.3 Immune system suppressors** 

effectiveness may wear off over time.

**2.2 Corticosteroids** 

Cyclosporine (Neoral, Sandimmune), a potent drug, is normally reserved for people who don't respond well to other medications or who face surgery because of severe UC.

Published trials evaluating the efficacy of 6-thioguanine anti-metabolites in the treatment of UC have yielded conflicting results. Leung *et al* [30] performed a systematic review and meta-analysis to evaluate the clinical efficacy of 6-thioguanine anti-metabolites for the maintenance of clinical remission after standard induction with corticosteroids. A comprehensive search of online databases was conducted. Only randomized controlled trials with 6-thioguanine antimetabolites within a minimum duration of follow-up of 6 months were selected. Five trials were included in the meta-analysis. Pooled results demonstrated a modest efficacy of azathioprine (AZA) for the treatment of ulcerative colitis. However, the use of AZA for the management of UC is not based on high-quality evidence.

There remains controversy regarding the efficacy of thiopurine analogs (AZA and 6-MP), methotrexate (MTX), and cyclosporine for the treatment of inflammatory bowel disease (IBD). An updated systematic review of the literature to clarify the efficacy of immunosuppressive therapy at inducing remission and preventing relapse in UC and CD was performed. Most evidence relates to AZA/6-MP where there is no statistically significant benefit at inducing remission in active CD and UC. Thiopurine analogs may prevent relapse in quiescent UC and CD. However, there is a paucity of data for immunosuppressive therapy in IBD and more research is needed [31].

Over the last decade, the increasing knowledge on the pathogenic mechanisms underlying intestinal inflammation has led to the development of a number of biological agents, mainly addressed to molecules and/or pathways demonstrated to have a pathogenic role in UC. In UC, clinical course and therapeutic decisions mainly depend on disease activity and extent. While therapeutic approach to mild-to-moderate UC by using aminosalicylates and corticosteroids has been well established, treatment of severe UC is far from being satisfactory. A severe attack of UC remains a challenge to be managed jointly by gastroenterology, surgery, and intensive care units. However, the recent introduction of biological therapies has led to promising changes in the management of UC patients. Aim of this paper is to review the recent advances and future perspectives for the use of biological agents in UC [32, 33]. Side effects of cyclosporine include high blood pressure, renal function impairment, and tingling sensations in the extremities. More serous side effects include anaphylactic shock and seizures.

Mucosal macrophages play an important role in the mucosal immune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major contributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD [34-36].

Progress has occurred in all major areas relevant to IBD pathogenesis, which include the external environment, genetics, microbial factors, and the immune system. This review presents an update on the specific major advances that have occurred in each of these four areas, briefly discusses the therapeutic implications of the observed progress, and points out the additional work that needs to be accomplished in the next few years to reach a full understanding of IBD etiopathogenesis [35,36].

Drug Therapy in Ulcerative Colitis 41

enemas in UC have shown clinical benefit, but controlled trials are needed. Mechanisms responsible for the association of smoking with colitis and for the therapeutic effect of nicotine remain an enigma; possibilities include: modulation of the immune response, alterations of colonic mucus and eicosanoid production, changes in rectal blood flow, decreased intestinal permeability and the release of endogenous glucocorticoids [19-22]. Smoking has been associated with a decreased frequency of UC. Currently, the role of nicotine for the treatment of UC is not established. Several studies have evaluated nicotine gum and transdermal patches as supplemental therapy for stable UC, but nicotine has not been compared with other treatment modalities. Nicotine dosages in the studies have varied from 5 to 30 mg/d without apparent dose-related therapeutic effects, and many patients have found relief from placebo treatment. Patients often do not tolerate nicotine therapy's adverse effects, such as nausea, light-headedness, and headache. Due to the cyclic disease course of UC and the potential addictiveness of nicotine, further large studies are warranted

There are significant proportions of patients with UC who experience adverse effects with current therapies. Consequently, new alternatives for the treatment of UC are constantly being sought. Probiotics are live microbial feed supplements that may beneficially affect the host by improving intestinal microbial balance, enhancing gut barrier function and improving local immune response. Mallon *et al* [12] assessed the efficacy of probiotics compared with placebo or standard medical treatment (5-aminosalicylates, sulfasalazine or corticosteroids) for the induction of remission in active ulcerative colitis. A comprehensive search for relevant randomised controlled trials (RCT's) was carried out using MEDLINE (1966-January 2006), EMBASE (January 1985- 2006) and CENTRAL. The Cochrane IBD/FBD Review Group Specialised Trials Registrar was also searched. The Australasian Medical Index, Chinese Biomedical Literature Database, Latin American Caribbean Health Sciences Literature (LILACS), and the Japan Information Centre of Science and Technology File on Science, Technology and Medicine (JICST-E) were also used to identify abstracts. Conference proceedings from the Falk Symposium, Digestive Disease Week (DDW) and the United European Digestive Disease week were hand-searched. Authors of relevant studies and drug companies were contacted regarding ongoing or unpublished trials that may be relevant to the review. However, there is limited evidence that probiotics added to standard therapy may provide modest benefits in terms of reduction of disease activity in patients with mild to moderately severe UC. Whether probiotics are as effective in patients with severe and more extensive disease and whether they can be used as an alternative to

Heparin is a naturally-occurring anticoagulant produced by basophils and mast cells. Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to

An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by

to assess the benefits of nicotine therapy for UC [29].

existing therapies is unknown [12].

work normally to break down clots that have formed.

**2.5 Heparin** 

VSL#3 (VSL#3) is a high-concentration probiotic preparation of eight live freeze-dried bacterial species that are normal components of the human gastrointestinal microflora, including four strains of lactobacilli (*Lactobacillus casei, L. plantarum, L. acidophilus,* and *L. delbrueckii* subsp*. bulgaricus*), three strains of bifidobacteria, and *Streptococcus salivarius* subsp. thermophilus. Data from noncomparative trials suggest that VSL#3 has clinical potential in the treatment of active mild to moderate ulcerative colitis and as maintenance therapy for patients with ulcerative colitis in remission. In addition, a randomized, openlabelled, multicenter trial showed that VSL#3 in combination with low-dose balsalazide (a prodrug of mesalazine [mesalamine; 5-ASA]) was more effective than standard doses of basalazide or mesalazine monotherapy in the treatment of acute mild to moderate ulcerative colitis. Randomized, double-blind, placebo-controlled studies have shown that VSL#3 is effective in preventing the onset of acute pouchitis in patients with newly formed surgical pouches, and in maintaining remission following antibacterial treatment of acute pouchitis in patients with a history of refractory or recurrent pouchitis. Treatment guidelines from the US and the UK include VSL#3 as a therapeutic option for the prevention of pouchitis relapse in patients with chronic pouchitis. In general, VSL#3 was well tolerated in clinical trials. Large, well designed, controlled confirmatory clinical trials will further determine the place of VSL#3 in the treatment of UC [18].

#### **2.4 Nicotine**

The skin patches seem to provide short-term relief from flare-ups of UC for some people, especially people who formerly smoked. How nicotine patches work isn't exactly clear, and the evidence that they provide relief is contested among researchers.

UC is characterized by impairment of the epithelial barrier and the formation of ulcer-type lesions, which result in local leaks and generalized alterations of mucosal tight junctions. Ultimately, this results in increased basal permeability. Although disruption of the epithelial barrier in the gut is a hallmark of inflammatory bowel disease and intestinal infections, it remains unclear whether barrier breakdown is an initiating event of UC or rather a consequence of an underlying inflammation, evidenced by increased production of proinflammatory cytokines. UC is less common in smokers, suggesting that the nicotine in cigarettes may ameliorate disease severity. The mechanism behind this therapeutic effect is still not fully understood, and indeed it remains unclear if nicotine is the true protective agent in cigarettes. Nicotine is metabolized in the body into a variety of metabolites and can also be degraded to form various breakdown products. Possibly, these metabolites or degradation products may be the true protective or curative agents. A greater understanding of the pharmacodynamics and kinetics of nicotine in relation to the immune system and enhanced knowledge of gut permeability defects in UC are required to establish the exact protective nature of nicotine and its metabolites in UC. This review suggests possible hypotheses for the protective mechanism of nicotine in UC, highlight the relationship between gut permeability and inflammation, and indicates where in the pathogenesis of the disease nicotine may mediate its effect [1-3, 12-14].

UC is predominantly a disease of non-smokers, and nicotine may be the agent responsible for this association. Transdermal nicotine has been shown to improve disease activity and sigmoidoscopic appearance in the active disease, but in one study it had no effect on maintenance of remission. Since side-effects with nicotine patches occur in up to two thirds of patients, attempts to reduce systemic levels and improve drug tolerance have been developed with colonic delivery systems of nicotine. Preliminary observations with nicotine

VSL#3 (VSL#3) is a high-concentration probiotic preparation of eight live freeze-dried bacterial species that are normal components of the human gastrointestinal microflora, including four strains of lactobacilli (*Lactobacillus casei, L. plantarum, L. acidophilus,* and *L. delbrueckii* subsp*. bulgaricus*), three strains of bifidobacteria, and *Streptococcus salivarius* subsp. thermophilus. Data from noncomparative trials suggest that VSL#3 has clinical potential in the treatment of active mild to moderate ulcerative colitis and as maintenance therapy for patients with ulcerative colitis in remission. In addition, a randomized, openlabelled, multicenter trial showed that VSL#3 in combination with low-dose balsalazide (a prodrug of mesalazine [mesalamine; 5-ASA]) was more effective than standard doses of basalazide or mesalazine monotherapy in the treatment of acute mild to moderate ulcerative colitis. Randomized, double-blind, placebo-controlled studies have shown that VSL#3 is effective in preventing the onset of acute pouchitis in patients with newly formed surgical pouches, and in maintaining remission following antibacterial treatment of acute pouchitis in patients with a history of refractory or recurrent pouchitis. Treatment guidelines from the US and the UK include VSL#3 as a therapeutic option for the prevention of pouchitis relapse in patients with chronic pouchitis. In general, VSL#3 was well tolerated in clinical trials. Large, well designed, controlled confirmatory clinical trials will further determine the place

The skin patches seem to provide short-term relief from flare-ups of UC for some people, especially people who formerly smoked. How nicotine patches work isn't exactly clear, and

UC is characterized by impairment of the epithelial barrier and the formation of ulcer-type lesions, which result in local leaks and generalized alterations of mucosal tight junctions. Ultimately, this results in increased basal permeability. Although disruption of the epithelial barrier in the gut is a hallmark of inflammatory bowel disease and intestinal infections, it remains unclear whether barrier breakdown is an initiating event of UC or rather a consequence of an underlying inflammation, evidenced by increased production of proinflammatory cytokines. UC is less common in smokers, suggesting that the nicotine in cigarettes may ameliorate disease severity. The mechanism behind this therapeutic effect is still not fully understood, and indeed it remains unclear if nicotine is the true protective agent in cigarettes. Nicotine is metabolized in the body into a variety of metabolites and can also be degraded to form various breakdown products. Possibly, these metabolites or degradation products may be the true protective or curative agents. A greater understanding of the pharmacodynamics and kinetics of nicotine in relation to the immune system and enhanced knowledge of gut permeability defects in UC are required to establish the exact protective nature of nicotine and its metabolites in UC. This review suggests possible hypotheses for the protective mechanism of nicotine in UC, highlight the relationship between gut permeability and inflammation, and indicates where in the

UC is predominantly a disease of non-smokers, and nicotine may be the agent responsible for this association. Transdermal nicotine has been shown to improve disease activity and sigmoidoscopic appearance in the active disease, but in one study it had no effect on maintenance of remission. Since side-effects with nicotine patches occur in up to two thirds of patients, attempts to reduce systemic levels and improve drug tolerance have been developed with colonic delivery systems of nicotine. Preliminary observations with nicotine

the evidence that they provide relief is contested among researchers.

pathogenesis of the disease nicotine may mediate its effect [1-3, 12-14].

of VSL#3 in the treatment of UC [18].

**2.4 Nicotine** 

enemas in UC have shown clinical benefit, but controlled trials are needed. Mechanisms responsible for the association of smoking with colitis and for the therapeutic effect of nicotine remain an enigma; possibilities include: modulation of the immune response, alterations of colonic mucus and eicosanoid production, changes in rectal blood flow, decreased intestinal permeability and the release of endogenous glucocorticoids [19-22].

Smoking has been associated with a decreased frequency of UC. Currently, the role of nicotine for the treatment of UC is not established. Several studies have evaluated nicotine gum and transdermal patches as supplemental therapy for stable UC, but nicotine has not been compared with other treatment modalities. Nicotine dosages in the studies have varied from 5 to 30 mg/d without apparent dose-related therapeutic effects, and many patients have found relief from placebo treatment. Patients often do not tolerate nicotine therapy's adverse effects, such as nausea, light-headedness, and headache. Due to the cyclic disease course of UC and the potential addictiveness of nicotine, further large studies are warranted to assess the benefits of nicotine therapy for UC [29].

There are significant proportions of patients with UC who experience adverse effects with current therapies. Consequently, new alternatives for the treatment of UC are constantly being sought. Probiotics are live microbial feed supplements that may beneficially affect the host by improving intestinal microbial balance, enhancing gut barrier function and improving local immune response. Mallon *et al* [12] assessed the efficacy of probiotics compared with placebo or standard medical treatment (5-aminosalicylates, sulfasalazine or corticosteroids) for the induction of remission in active ulcerative colitis. A comprehensive search for relevant randomised controlled trials (RCT's) was carried out using MEDLINE (1966-January 2006), EMBASE (January 1985- 2006) and CENTRAL. The Cochrane IBD/FBD Review Group Specialised Trials Registrar was also searched. The Australasian Medical Index, Chinese Biomedical Literature Database, Latin American Caribbean Health Sciences Literature (LILACS), and the Japan Information Centre of Science and Technology File on Science, Technology and Medicine (JICST-E) were also used to identify abstracts. Conference proceedings from the Falk Symposium, Digestive Disease Week (DDW) and the United European Digestive Disease week were hand-searched. Authors of relevant studies and drug companies were contacted regarding ongoing or unpublished trials that may be relevant to the review. However, there is limited evidence that probiotics added to standard therapy may provide modest benefits in terms of reduction of disease activity in patients with mild to moderately severe UC. Whether probiotics are as effective in patients with severe and more extensive disease and whether they can be used as an alternative to existing therapies is unknown [12].

#### **2.5 Heparin**

Heparin is a naturally-occurring anticoagulant produced by basophils and mast cells. Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed.

An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by

Drug Therapy in Ulcerative Colitis 43

UC. Treatment of chronic UC by traditional Chinese and Western medicine is safe and

Stimulation of acupuncture not only enhances the immune modulation effect, but also mobilizes the innate healing power inside the body. For the localized problems like inflammation, ulcers, muscular spasms and sluggish flow, acupuncture and moxibustion are particularly effective and thus facilitate structural recovery [41, 42]. Major points are navel's four-point (one-thumb-width apart from the navel, located in three, six, nine & twelve o'clock), *tian-shu, guan-yuan* & *qi-hai*; Assist points are *da-chang-shu, zhang-qiang, pi-shu, weishu, zu-san-li* & *san-yin-jiao.* When applying, firstly the four-point needle should be punctured in 0.3-0.5 cm deep 30-second for about rotations, with stimulation of the four locations in a clockwise sequence, without needle retention. Then one more major point and 2 to 3 assist points should be selected for stimulation, with the needles retaining on the locations for 15-20 minutes, and the moxa cones can be attached for heating during this time. Procedure is performed once daily or every two days with ten times is one course [2, 42]. Moxibustion can also be used to boost the weakened systems, particularly for individuals with chronic symptoms. Below are suggested protocols. The major points are *zhong-wan, tian-shu, guan-yuan* & *shang-ju-xu, and the* assist points are *pi-shu, shen-shu, da-chang-shu, zusan-li, tai-xi, tai-chong, san-yin-jiao* & *zhong-iv-shu*. Each time, 1-2 major points should be selected with heat for 30-40 minutes, while 2-3 assist points should be punctured with heat for 15-20 minutes. This procedure is performed once daily or every two days, with 15-20

Acupuncture-type treatments are among the most popular options. Several studies have reported that moxibustion is effective in ulcerative colitis (UC). The objective of this review was to assess the clinical evidence for or against moxibustion as a treatment for UC. Lee *et al* [43] searched the literature using 18 databases from their inception to February 10, 2010, without language restrictions. Randomized clinical trials (RCTs) were included, in which human patients with UC were treated with moxibustion. Studies were included if they were placebo-controlled or controlled against a drug therapy or no treatment group. The methodological quality of all RCTs was assessed using the Cochrane risk of bias. In total, five RCTs were included. All were of low methodological quality. They compared the effects of moxibustion with conventional drug therapy. Three tested moxibustion against sulfasalazine and two against sulfasalazine plus other drugs. A meta-analysis of five RCTs showed favorable effects of moxibustion on the response rate compared to conventional drug therapy (n = 407; risk ratio = 1.24, 95% CI = 1.11 to 1.38; P < 0.0001; heterogeneity: I2 = 16%). The results showed that current evidence is insufficient to show that moxibustion is an effective treatment of UC. Most of included trials had high risk of bias. More rigorous

In addition to controlling inflammation, some medications may help relieve the signs and symptoms. Depending on the severity of UC, the patients are recommended one or more of

**Antidiarrheals:** A fiber supplement such as psyllium powder (Metamucil) or methylcellulose (Citrucel) can help relieve signs and symptoms of mild to moderate diarrhea by adding bulk to the stool. For more severe diarrhea, loperamide (Imodium) may be effective. Use anti-diarrheal medications with great caution, however, because they

**Laxatives:** In some cases, swelling may cause the intestines to narrow, leading to

effective in maintaining remission [39, 40].

times in one course.

studies seem warranted.

the following [2, 8, 18-21].

constipation.

increase the risk of toxic megacolon.

extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC [37].

#### **2.6 Interferons**

Interferons (IFNs) are cytokines which possess immunoregulatory properties and have been used to successfully treat a number of chronic inflammatory disorders. It has been postulated that Type I IFNs may be able to re-establish the Th1/Th2 balance in Th2 predominant diseases like ulcerative colitis.

Seow *et al* [38] reported that four studies were eligible for inclusion. Three studies compared type I IFNs to placebo and a single study compared IFNs to prednisolone enemas in patients with left-sided colitis. Meta-analysis was based on the three IFN-placebo studies. There was no significant benefit of type I IFNs over placebo for inducing remission in ulcerative colitis (RR 1.24; 95% CI 0.81 to 1.90). There were no statistically significant differences in any of the secondary outcome variables. Conclusions were suggested by Seow *et al* [38] that the existing literature does not support the efficacy of type I IFNs for induction of remission in patients with UC. Given concerns regarding the tolerability of IFN therapy, we suggest that the results of two ongoing trials are evaluated for efficacy and safety prior to development or commencement of further randomised controlled trials of type I IFNs in UC.

#### **3. Treatment of traditional Chinese medicine**

Traditional Chinese medicine (TCM) believes that the major pathologies of UC include spleen and stomach dysfunctions, intestinal turbid accumulations, and blood and qi disturbances. Therefore, TCM treatment strategies are to restore organ functioning, eliminate turbid accumulations and harmonize the flows of qi and blood. In clinical applications, if individuals have obvious pus, mucus or bloody loose bowels, physicians will focus on clearing pathogens like damp-heat or damp-cold, so as to improve the bowel environment. Afterwards, notifying methods are employed to overcome the internal weakness and promote a longer remission period [2, 39-42].

Chinese medicine is getting more and more popular nowadays in the whole world for improving health condition of human beings as well as preventing and healing diseases. Chinese medicine is a multi-component system with components mostly unknown, and only a few compounds are responsible for the pharmaceutical and/or toxic effects. The large numbers of other components in the Chinese medicine make the screening and analysis of the bioactive components extremely difficult. So, separation and analysis of the desired chemical components in Chinese medicine are very important subjects for modernization research of Chinese medicine. Thus, many novel separation techniques with significant advantages over conventional methods were introduced and applied for separation and analysis of the chemical constituents in Chinese medicine. This review presents just a brief outline of the applications of different separation methods for the isolation and analysis of Chinese medicine constituents [2, 7]. Chinese medicine was widely used in the treatment of

extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible

Interferons (IFNs) are cytokines which possess immunoregulatory properties and have been used to successfully treat a number of chronic inflammatory disorders. It has been postulated that Type I IFNs may be able to re-establish the Th1/Th2 balance in Th2

Seow *et al* [38] reported that four studies were eligible for inclusion. Three studies compared type I IFNs to placebo and a single study compared IFNs to prednisolone enemas in patients with left-sided colitis. Meta-analysis was based on the three IFN-placebo studies. There was no significant benefit of type I IFNs over placebo for inducing remission in ulcerative colitis (RR 1.24; 95% CI 0.81 to 1.90). There were no statistically significant differences in any of the secondary outcome variables. Conclusions were suggested by Seow *et al* [38] that the existing literature does not support the efficacy of type I IFNs for induction of remission in patients with UC. Given concerns regarding the tolerability of IFN therapy, we suggest that the results of two ongoing trials are evaluated for efficacy and safety prior to development

Traditional Chinese medicine (TCM) believes that the major pathologies of UC include spleen and stomach dysfunctions, intestinal turbid accumulations, and blood and qi disturbances. Therefore, TCM treatment strategies are to restore organ functioning, eliminate turbid accumulations and harmonize the flows of qi and blood. In clinical applications, if individuals have obvious pus, mucus or bloody loose bowels, physicians will focus on clearing pathogens like damp-heat or damp-cold, so as to improve the bowel environment. Afterwards, notifying methods are employed to overcome the internal

Chinese medicine is getting more and more popular nowadays in the whole world for improving health condition of human beings as well as preventing and healing diseases. Chinese medicine is a multi-component system with components mostly unknown, and only a few compounds are responsible for the pharmaceutical and/or toxic effects. The large numbers of other components in the Chinese medicine make the screening and analysis of the bioactive components extremely difficult. So, separation and analysis of the desired chemical components in Chinese medicine are very important subjects for modernization research of Chinese medicine. Thus, many novel separation techniques with significant advantages over conventional methods were introduced and applied for separation and analysis of the chemical constituents in Chinese medicine. This review presents just a brief outline of the applications of different separation methods for the isolation and analysis of Chinese medicine constituents [2, 7]. Chinese medicine was widely used in the treatment of

or commencement of further randomised controlled trials of type I IFNs in UC.

increased risk of rectal bleeding in patients with active UC [37].

predominant diseases like ulcerative colitis.

**3. Treatment of traditional Chinese medicine** 

weakness and promote a longer remission period [2, 39-42].

**2.6 Interferons** 

UC. Treatment of chronic UC by traditional Chinese and Western medicine is safe and effective in maintaining remission [39, 40].

Stimulation of acupuncture not only enhances the immune modulation effect, but also mobilizes the innate healing power inside the body. For the localized problems like inflammation, ulcers, muscular spasms and sluggish flow, acupuncture and moxibustion are particularly effective and thus facilitate structural recovery [41, 42]. Major points are navel's four-point (one-thumb-width apart from the navel, located in three, six, nine & twelve o'clock), *tian-shu, guan-yuan* & *qi-hai*; Assist points are *da-chang-shu, zhang-qiang, pi-shu, weishu, zu-san-li* & *san-yin-jiao.* When applying, firstly the four-point needle should be punctured in 0.3-0.5 cm deep 30-second for about rotations, with stimulation of the four locations in a clockwise sequence, without needle retention. Then one more major point and 2 to 3 assist points should be selected for stimulation, with the needles retaining on the locations for 15-20 minutes, and the moxa cones can be attached for heating during this time. Procedure is performed once daily or every two days with ten times is one course [2, 42].

Moxibustion can also be used to boost the weakened systems, particularly for individuals with chronic symptoms. Below are suggested protocols. The major points are *zhong-wan, tian-shu, guan-yuan* & *shang-ju-xu, and the* assist points are *pi-shu, shen-shu, da-chang-shu, zusan-li, tai-xi, tai-chong, san-yin-jiao* & *zhong-iv-shu*. Each time, 1-2 major points should be selected with heat for 30-40 minutes, while 2-3 assist points should be punctured with heat for 15-20 minutes. This procedure is performed once daily or every two days, with 15-20 times in one course.

Acupuncture-type treatments are among the most popular options. Several studies have reported that moxibustion is effective in ulcerative colitis (UC). The objective of this review was to assess the clinical evidence for or against moxibustion as a treatment for UC. Lee *et al* [43] searched the literature using 18 databases from their inception to February 10, 2010, without language restrictions. Randomized clinical trials (RCTs) were included, in which human patients with UC were treated with moxibustion. Studies were included if they were placebo-controlled or controlled against a drug therapy or no treatment group. The methodological quality of all RCTs was assessed using the Cochrane risk of bias. In total, five RCTs were included. All were of low methodological quality. They compared the effects of moxibustion with conventional drug therapy. Three tested moxibustion against sulfasalazine and two against sulfasalazine plus other drugs. A meta-analysis of five RCTs showed favorable effects of moxibustion on the response rate compared to conventional drug therapy (n = 407; risk ratio = 1.24, 95% CI = 1.11 to 1.38; P < 0.0001; heterogeneity: I2 = 16%). The results showed that current evidence is insufficient to show that moxibustion is an effective treatment of UC. Most of included trials had high risk of bias. More rigorous studies seem warranted.

In addition to controlling inflammation, some medications may help relieve the signs and symptoms. Depending on the severity of UC, the patients are recommended one or more of the following [2, 8, 18-21].

**Antidiarrheals:** A fiber supplement such as psyllium powder (Metamucil) or methylcellulose (Citrucel) can help relieve signs and symptoms of mild to moderate diarrhea by adding bulk to the stool. For more severe diarrhea, loperamide (Imodium) may be effective. Use anti-diarrheal medications with great caution, however, because they increase the risk of toxic megacolon.

**Laxatives:** In some cases, swelling may cause the intestines to narrow, leading to constipation.

Drug Therapy in Ulcerative Colitis 45

The goal of drug therapy is to induce and maintain remission, and to improve the quality of life for people with ulcerative colitis. Several types of drugs are available. Drug treatment ulcerative colitis includes the following three categories: aminosalicylates, corticosteroids and immunomodulators. Other drugs may be given to relax the patient or to relieve pain,

These drugs that contain 5-aminosalicyclic acid (5-ASA) help control inflammation. Sulfasalazine is a combination of sulfapyridine and 5-ASA. The sulfapyridine component carries the anti-inflammatory 5-ASA to the intestine. However, sulfapyridine may lead to side effects such as nausea, vomiting, heartburn, diarrhea, and headache. Other 5-ASA agents, such as olsalazine, mesalamine, and balsalazide, have a different carrier, fewer side effects, and may be used by people who cannot take sulfasalazine. 5-ASAs are given orally, through an enema, or in a suppository, depending on the location of the inflammation in the colon. Most people with mild or moderate ulcerative colitis are treated with this group of

Corticosteroids such as prednisone, methylprednisone, and hydrocortisone also reduce inflammation. They may be used by patients who have moderate to severe UC or who do not respond to 5-ASA drugs. Corticosteroids, also known as steroids, can be given orally, intravenously, through an enema, or in a suppository, depending on the location of the inflammation. The drugs can cause side effects such as weight gain, acne, facial hair, hypertension, diabetes, mood swings, bone mass loss, and an increased risk of infection. For this reason, they are not recommended for long-term use, although they are considered very

These drugs such as azathioprine and 6-mercapto-purine (6-MP) reduce inflammation by affecting the immune system. Azathioprine and 6-MP are used for patients who have not responded to 5-ASAs or corticosteroids or who are dependent on corticosteroids. Immunomodulators are administered orally, however, patients are slow-acting and it may take up to 6 months before the full benefit. Patients taking these drugs are monitored for complications including pancreatitis, hepatitis, a reduced white blood cell count, and an increased risk of infection. Cyclosporine A may be used with 6-MP or azathioprine to treat

[1] Kozuch PL, Hanauer SB.Treatment of inflammatory bowel disease: a review of medical

[2] Xu CT, Meng SY, Pan BR. Drug therapy for ulcerative colitis.World J Gastroenterol.

[3] Karban A, Eliakim R. Effect of smoking on inflammatory bowel disease: Is it disease or organ specific? World J Gastroenterol. 2007;13(15):2150-2. PMID: 17465492

active, severe UC in patients who do not respond to intravenous corticosteroids.

therapy. World J Gastroenterol. 2008;14(3):354-77. PMID: 18200659

drugs first. This class of drugs is also used in cases of relapse.

effective when prescribed for short-term use.

2004;10(16): 2311-7. PMID: 15285010

diarrhea, or infection.

**5.1 Aminosalicylates** 

**5.2 Corticosteroids** 

**5.3 Immunomodulators** 

**6. References** 

**Pain relievers:** For mild pain, the patients recommend acetaminophen (Tylenol, others). Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be applied such as aspirin, ibuprofen (Advil, Motrin, others) or naproxen (Aleve). These are likely to make patient's symptoms worse.

**Iron supplements:** If patients have chronic intestinal bleeding, they may develop iron deficiency anemia. Taking iron supplements may help restore patient's iron levels to normal and reduce this type of anemia once the bleeding has stopped or diminished.

**Parenteral hyperalimentation:** For severe UC patients, it is one kind of security, the effective feasible method.

#### **4. Surgery**

Surgery is required in the vast majority of patients with CD and in approximately one-third of patients with UC. Similar to medical treatments for IBD, significant advances have occurred in surgery. Advances in CD include an emphasis upon conservatism as exemplified by more limited resections, strictureplasties, and laparoscopic resections. The use of probiotics in selected patients has improved the outcome in patients with pouchitis following restorative proctocolectomy for UC. It is anticipated that ongoing discoveries in the molecular basis of IBD will in turn identify those patients who will best respond to surgery [44]. Emergency surgery may be necessary for acute life-threatening attacks with massive bleeding, perforations, toxic megacolon, or blood clotting. Since the introduction of laparoscopy into colorectal surgery in the early 1990s, almost every procedure was attempted laparoscopically. Consequently, many very experienced surgical groups conducted numerous trials in an attempt to determine whether laparoscopy in IBD is indeed beneficial or not. The focus of this review is minimally invasive procedures in patients with UC [45].

#### **5. Summary**

Ulcerative colitis (UC) and Crohn's disease (CD) are two primary types of inflammatory bowel disease (IBD). UC is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is a main choice for UC treatment and medical management should be as a comprehensive one. Several types of medications are used to control the inflammation or reduce symptoms caused by ulcerative colitis. The treatment of UC depends on its severity, location and the presence of complications, so drug therapies must be custom-designed for each patient. Findings which medications best alleviate the symptoms may take time. The goal of medical treatment is to reduce the inflammation that triggers the signs and symptoms [2-4]. In the best cases, this may lead not only to symptom relief but also to longterm remission. Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-ASA, which is the topical anti-inflammatory ingredient. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds, systemic corticosteroids should be used. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved [13-15]. Surgery or immunomodulator is considered for patients with corticosteroid-dependent or unresponsive to corticosteroid treatment. Immunomodulators used for treating severe UC include azathioprine/6-MP, methotrexate, and cyclosporine [46-50]. Integrated traditional Chinese and Western medicine is safe and effective in maintaining remission in patients with UC.

**Pain relievers:** For mild pain, the patients recommend acetaminophen (Tylenol, others). Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be applied such as aspirin, ibuprofen (Advil, Motrin, others) or naproxen (Aleve). These are likely to make patient's

**Iron supplements:** If patients have chronic intestinal bleeding, they may develop iron deficiency anemia. Taking iron supplements may help restore patient's iron levels to normal

**Parenteral hyperalimentation:** For severe UC patients, it is one kind of security, the

Surgery is required in the vast majority of patients with CD and in approximately one-third of patients with UC. Similar to medical treatments for IBD, significant advances have occurred in surgery. Advances in CD include an emphasis upon conservatism as exemplified by more limited resections, strictureplasties, and laparoscopic resections. The use of probiotics in selected patients has improved the outcome in patients with pouchitis following restorative proctocolectomy for UC. It is anticipated that ongoing discoveries in the molecular basis of IBD will in turn identify those patients who will best respond to surgery [44]. Emergency surgery may be necessary for acute life-threatening attacks with massive bleeding, perforations, toxic megacolon, or blood clotting. Since the introduction of laparoscopy into colorectal surgery in the early 1990s, almost every procedure was attempted laparoscopically. Consequently, many very experienced surgical groups conducted numerous trials in an attempt to determine whether laparoscopy in IBD is indeed beneficial or not. The

Ulcerative colitis (UC) and Crohn's disease (CD) are two primary types of inflammatory bowel disease (IBD). UC is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is a main choice for UC treatment and medical management should be as a comprehensive one. Several types of medications are used to control the inflammation or reduce symptoms caused by ulcerative colitis. The treatment of UC depends on its severity, location and the presence of complications, so drug therapies must be custom-designed for each patient. Findings which medications best alleviate the symptoms may take time. The goal of medical treatment is to reduce the inflammation that triggers the signs and symptoms [2-4]. In the best cases, this may lead not only to symptom relief but also to longterm remission. Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-ASA, which is the topical anti-inflammatory ingredient. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds, systemic corticosteroids should be used. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved [13-15]. Surgery or immunomodulator is considered for patients with corticosteroid-dependent or unresponsive to corticosteroid treatment. Immunomodulators used for treating severe UC include azathioprine/6-MP, methotrexate, and cyclosporine [46-50]. Integrated traditional Chinese and Western

and reduce this type of anemia once the bleeding has stopped or diminished.

focus of this review is minimally invasive procedures in patients with UC [45].

medicine is safe and effective in maintaining remission in patients with UC.

symptoms worse.

**4. Surgery** 

**5. Summary** 

effective feasible method.

The goal of drug therapy is to induce and maintain remission, and to improve the quality of life for people with ulcerative colitis. Several types of drugs are available. Drug treatment ulcerative colitis includes the following three categories: aminosalicylates, corticosteroids and immunomodulators. Other drugs may be given to relax the patient or to relieve pain, diarrhea, or infection.

#### **5.1 Aminosalicylates**

These drugs that contain 5-aminosalicyclic acid (5-ASA) help control inflammation. Sulfasalazine is a combination of sulfapyridine and 5-ASA. The sulfapyridine component carries the anti-inflammatory 5-ASA to the intestine. However, sulfapyridine may lead to side effects such as nausea, vomiting, heartburn, diarrhea, and headache. Other 5-ASA agents, such as olsalazine, mesalamine, and balsalazide, have a different carrier, fewer side effects, and may be used by people who cannot take sulfasalazine. 5-ASAs are given orally, through an enema, or in a suppository, depending on the location of the inflammation in the colon. Most people with mild or moderate ulcerative colitis are treated with this group of drugs first. This class of drugs is also used in cases of relapse.

#### **5.2 Corticosteroids**

Corticosteroids such as prednisone, methylprednisone, and hydrocortisone also reduce inflammation. They may be used by patients who have moderate to severe UC or who do not respond to 5-ASA drugs. Corticosteroids, also known as steroids, can be given orally, intravenously, through an enema, or in a suppository, depending on the location of the inflammation. The drugs can cause side effects such as weight gain, acne, facial hair, hypertension, diabetes, mood swings, bone mass loss, and an increased risk of infection. For this reason, they are not recommended for long-term use, although they are considered very effective when prescribed for short-term use.

#### **5.3 Immunomodulators**

These drugs such as azathioprine and 6-mercapto-purine (6-MP) reduce inflammation by affecting the immune system. Azathioprine and 6-MP are used for patients who have not responded to 5-ASAs or corticosteroids or who are dependent on corticosteroids. Immunomodulators are administered orally, however, patients are slow-acting and it may take up to 6 months before the full benefit. Patients taking these drugs are monitored for complications including pancreatitis, hepatitis, a reduced white blood cell count, and an increased risk of infection. Cyclosporine A may be used with 6-MP or azathioprine to treat active, severe UC in patients who do not respond to intravenous corticosteroids.

#### **6. References**


Drug Therapy in Ulcerative Colitis 47

[22] Aberra FN, Lichtenstein GR.Infliximab in ulcerative colitis.Gastroenterol Clin North

[23] Ford AC, Achkar JP, Khan KJ, Kane SV, Talley NJ, Marshall JK, Moayyedi P. Efficacy of

[24] Nikfar S, Rahimi R, Rezaie A, Abdollahi M. A meta-analysis of the efficacy of

[25] Marshall JK, Thabane M, Steinhart AH, Newman JR, Anand A, Irvine EJ. Rectal 5-

[26] Ford AC, Bernstein CN, Khan KJ, Abreu MT, Marshall JK, Talley NJ, Moayyedi P.

[27] Chapman TM, Plosker GL, Figgitt DP.Spotlight on VSL#3 probiotic mixture in chronic inflammatory bowel diseases. Bio Drugs. 2007;21(1):61-3. PMID: 17263590 [28] Nakamura T, Nagahori M, Kanai T, Watanabe M.Current pharmacologic therapies and

[29] Cui HH, Chen CL, Wang JD, Yang YJ, Sun Y, Wang YD, Lai ZS.[The effects of

[30] Ingram JR, Thomas GA, Rhodes J, Green JT, Hawkes ND, Swift JL, Srivastava ED,

[31] Leung Y, Panaccione R, Hemmelgarn B, Jones J. Exposing the weaknesses: a systematic

[32] Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P. Efficacy of

[33] Danese S, Angelucci E, Malesci A, Caprilli R.Biological agents for ulcerative colitis:

[34] Aberra FN, Lichtenstein GR. Infliximab in ulcerative colitis. Gastroenterol Clin North

[35] Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in

[36] Fina D, Caruso R, Pallone F, Monteleone G.Interleukin-21 (IL-21) controls inflammatory

hypes and hopes. Med Res Rev. 2008; 28(2):201-18. PMID: 17464967

colitis.Zhonghua Nei Ke Za Zhi. 2003;42(8):554-7.PMID: 14505546

Database Syst Rev. 2010;(1):CD004115. PubMed PMID: 20091560

Gastroenterol. 2011;106(4):601-16. PubMed PMID: 21407188

Dis Sci. 2009;54(6):1157-70. PubMed PMID: 18770034

5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis. Am J

sulfasalazine in comparison with 5-aminosalicylates in the induction of improvement and maintenance of remission in patients with ulcerative colitis. Dig

aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane

Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):590-9; quiz 600. PubMed PMID:

emerging alternatives in the treatment of ulcerative colitis.Digestion. 2008;77(Suppl

bifidobacterium on the intestinal mucosa of the patients with ulcerative

Evans BK, Williams GT, Newcombe RG, Courtney E, Pillai S.A randomized trial of nicotine enemas for active ulcerative colitis.Clin Gastroenterol Hepatol.

review of azathioprine efficacy in ulcerative colitis. Dig Dis Sci. 2008;53(6):1455-61.

immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):630-42. PubMed PMID:

inflammatory bowel disease.World J Gastroenterol. 2008;14(27):4280-8. PMID:

pathways in the gut. Endocr Metab Immune Disord Drug Targets. 2007;7(4):288-91.

Am. 2006;35(4): 821-36. PMID: 17129815

21407179

1):36-41. PMID: 18204260

PMID: 17932752

21407186

18666314

PMID: 18220949

2005;3(11):1107-14. PMID: 16271342

Am. 2006; 35(4): 821-36. PMID: 17129815


[4] McGilligan VE, Wallace JM, Heavey PM, Ridley DL, Rowland IR.Hypothesis about

[5] Yun J, Xu CT, Pan BR. Epidemiology and gene markers of ulcerative colitis in the

[6] Jiang XL, Cui HF. An analysis of 10218 ulcerative colitis cases in China.World J

[7] Liu S, Yi LZ, Liang YZ.Traditional Chinese medicine and separation science. J Sep Sci.

[8] Xu CT, Pan BR.Current medical therapy for ulcerative colitis.World J Gastroenterol.

[9] Odes S. How expensive is inflammatory bowel disease? A critical analysis.World J

[10] Jess T. Prognosis of inflammatory bowel disease across time and countries. An

[11] Kale-Pradhan PB, Pradhan RS, Wilhelm SM.Multi-matrix system mesalamine: to use or

[12] Mallon P, McKay D, Kirk S, Gardiner K. Probiotics for induction of remission in

[13] Khan KJ, Ullman TA, Ford AC, Abreu MT, Abadir A, Marshall JK, Talley NJ, Moayyedi

analysis. Am J Gastroenterol. 2011;106(4):661-73. PubMed PMID: 21407187 [14] Gionchetti P, Rizzello F, Lammers KM, Morselli C, Tambasco R, Campieri M.

[15] Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis of antibiotic therapy for active ulcerative colitis. Dig Dis Sci. 2007;52(11):2920-5. PubMed PMID: 17415632 [16] Rahimi R, Nikfar S, Rezaie A, Abdollahi M. Comparison of mesalazine and balsalazide

meta-analysis. Dig Dis Sci. 2009;54(4):712-21. PubMed PMID: 18683049 [17] Hawthorne AB, Rubin G, Ghosh S.Review article: medication non-adherence in

[18] Swaminath A, Kornbluth A. Optimizing drug therapy in inflammatory bowel disease.

[19] Lakatos PL, Lakatos L. Effectiveness of new, once-daily 5-aminosalicylic acid in the

[20] Lakatos PL, Lakatos L.Ulcerative proctitis: a review of pharmacotherapy and management.Expert Opin Pharmacother. 2008 Apr;9(5):741-9. PMID: 18345952 [21] Jiang XL, Cui HF. Different therapy for different types of ulcerative colitis in

China.World J Gastroenterol. 2004;10(10):1513-20.PMID: 15133864

Curr Gastroenterol Rep. 2007;9(6):513-20. PMID: 18377805

not to use. Ann Pharmacother. 2008;42(2):265-9. PMID: 18182473

epidemiological study of population-based patient cohorts.Dan Med Bull.

ulcerative colitis. Cochrane Database Syst Rev. 2007;(4):CD005573. PMID: 17943867

P. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-

Antimicrobials in the management of inflammatory bowel disease. Digestion.

in induction and maintenance of remission in patients with ulcerative colitis: a

ulcerative colitis--strategies to improve adherence with mesalazine and other maintenance therapies. Aliment Pharmacol Ther. 2008;27(12):1157-66. PMID:

treatment of ulcerative colitis]. Orv Hetil. 2009;150(9):397-404. PubMed PMID:

2007;13(1):108-15. PMID: 17206646

PubMed Central PMCID: PMC2653379

2008;31(11): 2113-37. PMID: 18615809

1999;5(1):64-72. PMID: 11819390

2008;55(2):103-20.PMID: 19017498

18384664

19228568

Gastroenterol. 2002;8(1):158-61.PMID: 11833094

Gastroenterol. 2008; 14(43):6641-7.PMID: 19034966

2006;73(Suppl 1):77-85. PubMed PMID: 16498255

mechanisms through which nicotine might exert its effect on the interdependence of inflammation and gut barrier function in ulcerative colitis.Inflamm Bowel Dis.

Chinese. World J Gastroenterol. 2009;15(7):788-803. PubMed PMID:19230040;


**4** 

*Italy* 

**New Biologic Drugs for Ulcerative Colitis** 

*Gastrointestinal Unit, Department of Internal Medicine, University of Rome Tor Vergata,* 

Inflammatory bowel diseases (IBD) are chronic remittent or progressive inflammatory conditions that may affect the gastrointestinal tract. Crohn's disease (CD) and Ulcerative colitis (UC) are two main phenotypes of IBD. Their etiopathogenesis has not been elucidated but is thought to involve a complex interplay among genetic, environmental, microbial and immune response (1). In the last two decade the advances in our knowledge of the pathogenesis mechanism underlying chronic inflammation in the gut, together with the increase progress in biotechnology have led to the development of a number of biological agent that selectively target specific molecules and pathway involve in gut inflammation.

We briefly review the mechanism of action and the efficacy of biological agent in UC.

common single nucleotide polymorphisms of minor individual biologic impact.

The discordance of IBD among monozygotic twins and the development of IBD in immigrants to high prevalence countries and in countries under going rapid Westernization also highlight the importance of environmental factors in disease pathogenesis. Elements within a changing environmental that might affect development of the mucosal immune

Both types of IBD occur in genetically susceptible individuals. IBD, considered a polygenic disorder, is familial in 5-10% and sporadic in the remainder (2). In UC phenotypic concordance in monozygotic twins is less frequent (10-20%) than in CD (50-70%), suggesting that the environmental factors play a more important role. Genetic studies, including genome wide association studies (GWASs) have improved our knowledge on the importance of genetic susceptibility in IBD. Interesting GWASs revealed a substantial overlap in genetic risk factors between CD and UC (3). However it is possible that this similitude is not shared at the level of structurally or functionally relevant polymorphisms. However some loci are quite unique for UC or for CD. For example loci related to regulatory pathways (IL10) intestinal epithelial cell function (ECM1) and HERC2 appear to be specific for UC. A striking outcome of GWASs is that the vast majority of identified loci individually confer a modest risk (odds ratios 1.11 and 1.29). The genetic basis for sporadic IBD may be due to the cumulative effect of interaction of unknown quantities of potentially thousands of

**1. Introduction** 

**2. Pathogenetic background** 

**2.2 Genetics factors** 

**2.3 Environmental factors** 

Francesca Zorzi, Emma Calabrese and Francesco Pallone

