Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1515_Библиотеки_им_академика_М_И_Перельмана
.pdf
154 L. Zorcolo, G. Casula
serving total mesorectal excision. Surg Clin North Am
82:1009–1018
119. Slors FJ, van Zuijlen PP, van Dijk GJ (2000) Sexual and
bladder dysfunction after total mesorectal excision for
benign diseases. Scan J Gastroenterol 232:48–51
120. Velanovich V (1992) Pharmacologic prevention and
treatment of postoperative urinary retention. Infect
Urol 3:87
121. Goldman G, Kahn PJ, Kashtan HJ et al (1988) Preven-
tion and treatment of urinary retention and infection
after surgical treatment of the colon and rectum with
alpha adrenergic blockers. Surg Gynecol Obstet
166:447–450
122. Finkbeiner AE (1985) Is bethanechol chloride clinical-
ly effective in promoting bladder emptying? A litera-
ture review. J Urol 134:443–449
123. Del Rio C, Sanchez-Santos R, Oreja V et al (2004)
Long-term urinary dysfunction after rectal cancer sur-
gery. Colorectal Dis 6:198–202
124. Graham JW, Goligher JC (1954) The management of
accidental injuries and deliberate resections of the
ureter during excision of the rectum. Br J Surg
42:151–160
125. Dowling RA, Corriere JN Jr., Sandler CM (1986) Iatro-
genic ureteral injury. J Urol 135:912–915
126. Bothwell WN, Bleicher RJ, Dent TL (1994) Prophylac-
tic ureteral catheterization in colon surgery: a five-
year review. Dis Colon Rectum 37:330–334
127. Beahrs JR, Beahrs OH, Beahrs MM et al (1978) Urinary
tract complications with rectal surgery. Ann Surg
187:542–548
128. Lindsey I, George BD, Kettlewell MGW et al (2001)
Impotence after mesorectal and close rectal dissection
for inflammatory bowel disease. Dis Colon Rectum
44:831–835
129. Hamawy K, Smith JJ, Libertino JA (2000) Injuries of
the distal ureter. Seminars in Colon Rectal Surgery
11:163–179
130. Block GE, Hurst RD (1995) Complications of the sur-
gical treatment of ulcerative colitis and Crohn’s dis-
ease. In: Kirsner JB, Shorter RG (eds) Inflammatory
bowel disease, 4th edn. Williams, Baltimore, MD, pp
898–922
131. Metcalf AM, Dozois RR, Kelly KA (1986) Sexual func-
tion in women after proctocolectomy. Ann Surg
204:624–627
132. Damgaard B, Wettergreen A, Kirkegaard P (1995)
Social and sexual function following ileal pouch-anal
anasotomosis. Dis Colon Rectum 38:286–289
133. Berndtsson I, Oresland T, Hulten L (2004) Sexuality in
patients with ulcerative colitis before and after
restorative proctocolectomy: a prospective study.
Scand J Gastroenterol 39:374–379
134. Gorgun E, Remzi FH, Montague DK et al (2005) Male
sexual function improves after ileal pouch anal anas-
tomosis. Colorectal Dis 7:545–550
135. Gruner ON, Naas R, Fretheim B et al (1977) Marital
status and sexual adjustment after colectomy: results
in 178 patients operated on for ulcerative colitis. Scand
J Gastroenterol 12:193–197
136. Weber AM, Ziegler C, Belinson JL et al (1995) Gyneco-
logic history of women with inflammatory bowel dis-
ease. Obstet Gynecol 86:843–847
137. Sjogren B, Poppen B (1995) Sexual life in women after
colectomy-proctomucosectomy with S-pouch. Acta
Obstet Gynecol Scand 74:51–55
138. Ragni G, Bianchi Porro G, Ruspa M et al (1984).
Abnormal semen quality and lower serum testos-
terone in men with inflammatory bowel disease treat-
ed for a long time with sulfasalazine. Andro
16:162–167
139
. Riley SA, Lecarpentier J, Mani V (1987) Sulfasalazine
induced seminal abnormalities: results of mesalazine
substitution. Gut 28:1008–1012
140. Ireland A, Jewell DP (1989) Sulfasalazine-induced
impotence: a beneficial resolution with olsalazine? J
Clin Gastroenterol 11:711
141. Sagar PM, Lewis W, Holdsworth PJ et al (1993) Quali-
ty of life after restorative proctocolectomy with a
pelvic ileal reservoir compares favourably with that of
patients with medically treated colitis. Dis Colon Rec-
tum 36:584–592
142. Watts JM, de Dombal FT, Goligher JC (1966) Early
results of surgery for ulcerative colitis. Br J Surg
53:1005–1014
143. Corman ML, Veidenheimer MC, Coller JA (1978)
Impotence after proctectomy for inflammatory dis-
ease of the bowel. Dis Colon Rectum 21:418–419
144. Fazio VW, Fletcher J, Montague D (1980) Prospective
study of the effect of resection of the rectum on male
sexual function. World J Surg 4:149–152
145. Bauer JJ, Gelernt IM, Salky B et al (1983) Sexual dys-
function following proctocolectomy for benign disease
of the colon and rectum. Ann Surg 197:363–367
146. Tiainen J, Matikainen M, Hiltunen KM (1999) Ileal J-
pouch-anal anastomosis, sexual dysfunction, and fer-
tility. Scand J Gastroenterol 34:185–188
147. Dozois RR, Nelson H, Metcalf AM (1993) Sexual func-
tion after ileo-anal anastomosis. Ann Chir 47:1009–1013
148. Michelassi F, Stella M, Block GE (1993) Prospective
assessment of functional results after ileal J pouch-
anal restorative proctocolectomy. Arch Surg 128:889–895
149. Sorcini A, Vereb MJ (2000) Sexual and reproductive
complications after pelvic surgery. Seminars in Colon
Rectal Surgery 11:141–147
150. Lee EC, Dowling BL (1972) Perimuscular excision of
the rectum for Crohn’s disease. Br J Surg 59:29–32
151. Bauer JJ, Gelernt IM, Salk BA et al (1986) Proctectomy
for inflammatory bowel disease. Am J Surg
151:157–162
152. Little JA, Parks AG (1977) Intersphincteric excision of
the rectum. Br J Surg 64:413–416
153. Yeager ES, Van Heerden JA (1980) Sexual dysfunction
following proctocolectomy and abdominoperineal
resection. Ann Surg 191:169–170
154. Maurer CA, Z’Graggen K, Renzulli P et al (2001) Total
mesorectal excision preserves male genital function
compared with conventional rectal cancer surgery. Br
J Surg 88:1501–1505
155. Malloy TR, Wein AJ, Carpiniello VL (1986) Reliability
of AMS 700 inflatable penile prothesis. Urology
27:385–387
156. Benson GS (1996) Male sexual dysfunction—pitfalls,
pills and prostheses. J Urol 156:1636
157. Cameron MC, Gillett WR (1985) The recovery of
sperm, insemination and pregnancy in the treatment
Urinary and Sexual Involvement in IBD 155
of infertility because of retrograde ejaculation. Fertil
Steril 44:844–845
158. Shangold GA, Cantor B, Schreiber JR (1980) Treat-
ment of infertility due to retrograde ejaculates: a sim-
ple, cost-effective method. Fertil Steril 34:175–177
159. Thomas AJ Jr (2004) Infertility. J Urol 172(3):829–830
160. van Duijvendijk P, Slors JF, Taat CW et al (2000) What
is the benefit of preoperative sperm preservation for
patients who undergo restorative proctocolectomy for
benign diseases? Dis Colon Rectum 43:838–842
161. Wikland M, Jansson I, Asztely M et al (1990) Gyneco-
logical problems related to anatomical changes after
conventional proctocolectomy and ileostomy. Int J
Colorectal Dis 5:49–52
162. Sjodahl R, Nystrom P, Olaison G (1990) Surgical treat-
ment of dorsocaudal dislocation of the vagina after
excision of the rectum: the Kylberg operation. Dis
Colon Rectum 33:762–764
163. Oresland T, Palmblad S, Ellstrom M et al (1994) Gyne-
cological and sexual function related to anatomical
changes in the female pelvis after restorative procto-
colectomy. Int J Colorectal Disease 9:77–81
164. Sprangers MA, Taal BG, Aaronson NK, et al (1995).
Quality of life in colorectal cancer. Stoma vs. non-
stoma patients. Dis Colon Rectum 38:361–369
165. Nugent KP, Daniels P, Stewart B et al (1999) Quality of
life in stoma patients. Dis Colon Rectum 42:1569–1574
Introduction
Crohn’s Disease (CD) is a chronic inflammatory dis-
ease of the gastrointestinal tract, with a low percent-
age of patients remaining in clinical remission
despite the long-term use of many drugs (steroids,
immunosuppressants, aminosalicylates, antibiotics).
As a consequence of the limited efficacy and signifi-
cant toxicity of current therapy, there is widespread
interest in the development of novel drugs for the
clinical management of CD.
In the early 1990s, the pathogenetic mechanisms
of inflammatory bowel diseases (IBDs) were clarified.
Greater knowledge of systemic and local inflammato-
ry cascade of CD (T1-helper-driven inflammation)
[1] allowed identification of key mediators of inflam-
mation, and pharmacologic research was addressed
towards specific biologic drugs interfering with this
cascade. Proinflammatory cytokines play a central
role in amplification of the inflammatory process,
inducing release of other cytokines and increasing
the expression of adhesion molecules [2]. Tumour
necrosis factor (TNF)-α and interleukin (IL)-1 are
released at the beginning of the inflammatory cas-
cade and contribute to recruitment and activation of
inflammatory cells (macrophages, neutrophils,
monocytes) by increasing mucosal intestinal perme-
ability and stimulating the release of adhesion mole-
cules. Anti-inflammatory cytokines play an impor-
tant role in avoidance of an abnormal immune
response. In particular, IL-10 controls TNF produc-
tion, major histocompatibility complex (MHC)-II
expression and release of other inflammatory media-
tors whereas IL-12 induces the release of interferon
gamma (INF-γ) by macrophages and natural-killer
lymphocytes [3].
The term “biological agent” means any therapeu-
tic agent derived from a living organism. Therefore,
biological therapy may include [4]: (1) modified bio-
logical compounds (i.e. vaccine), hormones, etc.; (2)
recombinant peptides or proteins (i.e. growing fac-
tors, growth hormones, etc.); (3) monoclonal anti-
bodies or fusion proteins; (4) antisense oligonu-
cleotides. Many molecules have been used in con-
trolled or open trials, mainly in fistulising or steroid-
dependent CD (Table 1). Monoclonal antibodies and
antisense nucleotides interfering with messenger
ribonucleic acid (mRNA) are the drugs most fre-
quently tested in clinical trials.
The Present: Indications,Efficacy, Problems and
Open Fields Using Infliximab in Crohn’s Disease
The first drug approved by the Food and Drug
Administration for the treatment of CD was inflix-
imab (Remicade) [5], a monoclonal chimeric anti-
body (human 75%, murine 25%). Infliximab neu-
tralises biological activity of TNF-α by binding with
high affinity to both soluble and transmembrane
forms of TNF-α, inhibiting binding of TNF-α with its
receptors. Therefore, infliximab heavy reduces TNF-
α plasmatic levels and induces inflammatory cell
apoptosis in the gut wall [6–9], thus promoting
mucosal healing at colonoscopy [10, 11].
Efficacy on Remission and Maintenance Therapy
Infliximab, administrated intravenously at a dosage
of 5 mg/kg of body weight at weeks 0, 2 and 6 (induc-
tion therapy) and, later, every 8 weeks (maintenance
therapy) is effective in the therapy of patients with
active CD [12]. Infliximab is also a corticosteroid-
sparing drug in patients with active CD [13–15]. Def-
inite indications for induction therapy with inflix-
imab (eligible patients) are [13]: (1) Fibrostenosing
(inflammatory) disease nonrespondent or refractory
to steroid and conventional therapy; (2) fistulising
disease, draining enterocutaneous or perianal fistu-
lae.
The use of infliximab as first-line treatment of
patients with moderate to severe CD is still contro-
versial. There are no studies demonstrating the effi-
cacy of this scheduled therapy even though this
approach has been suggested [16].
Biological Approach in the Treatment of Crohn’s Disease
Luca Frulloni, Laura Bernardoni, Chiara Scattolini, Italo Vantini
158 L. Frulloni, L. Bernardoni, C. Scattolini, I. Vantini
Induction therapy is effective in up to 70% of
cases [10, 12, 17–30]. Not responders to induction
therapy do not respond to a maintenance therapy. In
patients who respond to induction therapy, mainte-
nance therapy may prolong complete clinical remis-
sion [Crohn’s Disease Activity Index (CDAI) <150]
after 1 year in about 40% of cases, with clinical
response in 60% of cases. This implies that, after 1
year of prolonged infliximab therapy, only 25% of
patients attain complete clinical remission and 35%
clinical response [10, 12, 17–29]. There is evidence
that an increase of infliximab dosage and/or a reduc-
tion of interval time between infusions may main-
tain a higher number of patients in clinical remis-
sion [21, 31–33].
Disease Type and Stage
The reported incidence of fistulae in patients with CD
ranges from 17% to 50% [34]. Fistulae may be ente-
rocutaneous (more commonly perianal), easily
recognisable; or internal, enteroenteric or between
gut and other organs. Internal fistulae may be asymp-
tomatic but may be more aggressive and require
urgent surgery (temporary colostomy allows the
Table 1. Biological therapy in Crohn’s disease
Proper name Trade name Action
Inhibitors of pro-inflammatory cytokines
Infliximab Remicade Chimeric (human/mouse) anti-TNF-
α monoclonal antibody
(IgG1)
CDP571 Humicade Humanized anti-TNF
α monoclonal antibody (IgG4)
Certolizumab - Humanized anti-TNF-
α monoclonal antibody (polyethylene
glycolated Fab’ fragment)
Adalimumab Humira Humanized anti-TNF-
α monoclonal antibody (IgG1)
Thalidomide Thalomid Derivative of glutamic acid with anti-inflammatory and
anti-TNF-
α action
Semapimod - Interferes with the phosphorylation of both p38 and JNK
Etanercept Enbrel Genetically engineered fusion protein consisting of two
identical chains of the recombinant human p75 TNF
receptor linked to the Fc portion of human IgG1
Onercept - Recombinant form of the human soluble p55 TNF receptor
MRA - Humanized monoclonal antibody to IL-6 receptor
ABT-874/J695 - Humanized anti-IL-12 p40 (IgG1)
Anti-inflammatory cytokines
RhIL-10 Tenovil Humanized monoclonal antibody to IL-10
RhIL-11 - Humanized monoclonal antibody to IL-11
Inhibitors of adhesion molecules
Alicaforsen - Antisense phosphorothioate oligonucleotide targeting human
ICAM-1 mRNA
Natalizumab Antegren Humanized monoclonal antibody against
α4 integrin
Immune modulators
Tacrolimus Prograf Inhibits production of IL- 2 by T-helper cells
Mycophenolate mofetil CellCept Antimetabolite strongly suppressing lymphocyte proliferation
Miscellaneous
Sargramostim Leukine Yeast-derived recombinant human GM-CSF
Trichuris suis - Worm
Probiotics VSL#3 Bacteria
TNF, tumor necrosis factor; IgG, immunoglobulin G; JNK, Jun N-terminal kinase; ICAM, intercellular adhesion molecule; mRNA, mes-
senger ribonucleic acid; IL, interleukin; GM-CSF, granulocyte macrophage colony stimulating factor
Biological Approach in the Treatment of Crohn’s Disease 159
patient to heal by bypassing the inflammatory tract).
In perianal disease, induction therapy with inflix-
imab (5 mg/kg at 0, 2 and 6 weeks) is effective on fis-
tula healing in more than 60% of patients [28, 35].
Concomitant conventional therapy (antibiotics and
immunosuppressants) is useful since 3 months’ treat-
ment with antibiotic monotherapy (metronidazole
and ciprofloxacin) showed 60–70% complete remis-
sion, improved quality of life and reduced disease
recurrences [20, 36, 37]. Azathioprine monotherapy is
effective as well, but its full action is evident after 2–3
months of therapy. Therefore, its use in fistulising
(perforating) CD is limited, at least as initial treat-
ment. In patients intolerant to azathioprine,
methotrexate at dose of 25 mg intramuscularly week-
ly may be a possible alternative treatment [38].
In patients with perianal fistulae, first-line treat-
ment with antibiotics is suggested. In case of relapse,
antibiotics and immunosuppressant therapy (aza-
thioprine or methotrexate) is effective. If fistulae per-
sist, induction therapy with infliximab is recom-
mended, followed by maintenance therapy with
immunosuppressant or infliximab (every 8 weeks)
[36, 39].
In our opinion, a more appropriate first-line treat-
ment may include induction therapy with infliximab,
followed in responders by a maintenance regimen
with infliximab and introduction of immunosup-
pressant drugs. In nonresponders or those intolerant
to infliximab i.v., antibiotics, immunosuppressants
and local injection of infliximab may be an alterna-
tive treatment [40]. Internal fistulae are usually asso-
ciated to a more aggressive subtype of CD and more
difficult to treat conservatively [41]. However, treat-
ment with azathioprine and antibiotics or infliximab
may be tried [42, 43].
In some patients, clinical onset of CD occurs with
subocclusive symptoms secondary to inflammatory
strictures. In naïve patients, infliximab probably
induces rapid anti-inflammatory effects with symp-
tomatic improvement, reducing the need for resec-
tive surgery. There are no studies confirming this
hypothesis but a top-down therapy has been recently
proposed [16] and, probably, in the near future, this
may be an appropriate initial treatment [44]. Howev-
er, concomitant therapy with immunomodulators
increases the rate of clinical response and clinical
remission, and smoking seems to be a negative pre-
dictor of response to infliximab therapy [45, 46].
Therefore, an initial therapeutic approach with
steroids and immunosuppressants followed by inflix-
imab is suggested, as well as smoking cessation.
On the contrary, infliximab is not indicated in the
presence of a fibrotic stenosis [44, 47]. Clinical (long-
standing disease), laboratory data [inflammatory
indexes, mainly C-reactive protein [48, 49] and instru-
mental findings by magnetic resonance imaging
(MRI) or fluorodeoxyglucose positron emission
tomography (FDG-PET)] may help in discriminating
an inflammatory or fibrotic process in the intestinal
wall [47].
Finally, infliximab significantly improved quality
of life in patients with active CD, increasing their
ability to work and significantly reducing hospitali-
sations, surgeries and procedures compared with
placebo [50–55].
Adverse Events and Side Effects
Infliximab is a drug with low side effects. Up to now,
more than 300,000 patients have been treated with
infliximab for rheumatoid arthritis and CD [56]. The
more frequent side effects, generally mild, are
headache, nausea, upper respiratory infections, skin
rash and diarrhoea. However, the incidence of these
side effects is similar to that observed in the placebo
group, except for upper respiratory infections, which
are more common in patients treated with infliximab
[23, 56–58].
Adverse events include acute and delayed hyper-
sensitivity reactions. Acute reactions (1–20%) appear
during or within 2 h of infusion and are not
immunoglobulin E (IgE) mediated. They include
headache, nausea, dyspnea, urticaria and coercion
chest perception. Treatment of acute reactions con-
sists of temporarily stopping the infusion, adminis-
trating antihistamine drugs and/or steroids and then
restart infusion at a low rate [13, 22, 23, 57–59]. If
acute reactions recur, retreatment is not recom-
mended [13]. Delayed hypersensitivity reactions
occur after 3–12 days after infusion in 2–3% of
patients. Generally, these reactions are serious and
consist in itch, headache, swelling of hands or face,
rash, myalgia, polyarteritis, fever and leucocytosis.
Steroids induce complete and immediate resolution
of symptoms without recurrences. When delayed
hypersensitivity reaction occurs, retreatment is not
recommended.
Adverse events are caused by the development of
antibodies to infliximab (ATI) related to its chimeric
nature as it consists of 25% murine proteins. The
incidence of ATI is low (10–20%) and at low titre [12,
60, 61]. The presence of ATI reduces drug efficacy in
term of percentage of active response (clinical remis-
sion) and duration of effectiveness (lower in patients
who develop ATI) [12, 62]. Strategies to decrease ATI
production are:
– scheduled therapy (not “on demand”): single dose
or sporadic infusion causes higher incidence of
ATI [30, 63, 64].
– Steroids pretreatment before infliximab infusion
160 L. Frulloni, L. Bernardoni, C. Scattolini, I. Vantini
(particularly in the induction phase): hydrocorti-
sone 100 mg i.v. [60, 65].
– Two- to four-month immunosuppressant pre-
treatment before first infliximab infusion: azathio-
prine 2 mg/kg per day [57, 65, 66].
Risks: Infections, Tumours, Heart and Neurologic Diseases
TNF-α plays an essential role in the immune-mediat-
ed response against infection, especially towards
intracellular pathogens [67–70]. Many data support
the association between TNF-α blockers and infec-
tions [71–74]. Susceptibility to all types of infections
is higher, particularly upper respiratory tract infec-
tions and bacterial skin infections [74, 75]. TNF-α
antagonists should not be given to patients with
active infections. Severe pulmonary and abdominal
infections (pneumonia, abdominal abscess) are more
frequently observed in patients treated with inflix-
imab than placebo.
Many reactivation cases of pulmonary and extra-
pulmonary tuberculosis have been reported during
the first 3 months of infliximab therapy [72, 76–78].
Screening for tuberculosis (skin test and chest X-ray)
before anti-TNF therapy is strongly recommended
[67, 76]. Some authors suggested that if the skin test
is negative, treatment with infliximab may be given
without prophylactic therapy. If the skin test is posi-
tive, an accurate clinical history, physical examina-
tion and chest X-ray are required to rule out active
disease [67]. However, it should be considered that:
(1) a concomitant use of steroids or immunosup-
pressant drugs may interfere with the skin test; (2) a
large number of patients with IBD are anergic, with a
delayed hypersensitivity reaction; (3) more than 15%
of patients with active tuberculosis (TBC) infection
are anergic; (4) more than 90% of patients with posi-
tive skin test have a negative chest X-ray. Therefore,
an accurate clinical history, skin test and chest X-ray
are mandatory before infliximab administration in
all cases. In the absence of tuberculosis lesions at
chest X-ray but with a clinical history suggestive for
TBC and/or in patients at strong risk for TBC infec-
tion (immigrant, injection-drug users, HIV patients,
diabetes mellitus, etc.) empirical isoniazid for 6–9
months is a reasonable prophylactic treatment, start-
ing infliximab after 2 months if clinically required. In
the presence of TBC lesions at chest X-ray, active
therapy is mandatory for at least 2 months before
infliximab therapy.
Very rare cases (less than 0.01%) of fungal infec-
tion (cryptococcosis, coccidioidomycosis, listeriosis
and histoplasmosis) during infliximab therapy are
reported [71, 73, 79–94]. Screening and primary pro-
phylaxis are not recommended, but patients with a
history of these infections can receive secondary pro-
phylaxis with oral fluconazole.
Patients eligible for infliximab therapy should be
tested for hepatitis B and C serological markers
before treatment. It has been documented that TNF-
α levels are increased in patients with viral hepatitis
[95, 96]. Inhibition of TNF-α may alter host antiviral
defence mechanisms and promote virological repli-
cation [97]. The safety of infliximab in hepatitis C has
been demonstrated in a retrospective study on
patients with rheumatoid arthritis, as well as in case
reports [98
–102]. In hepatitis B, reactivation of infec-
tion has been documented, as has a case of fulminat-
ing hepatitis B after one infusion of infliximab [97,
103–107]. However, definitive conclusions cannot be
made regarding the use of infliximab in patients suf-
fering from viral hepatitis. If infliximab therapy is
necessary in patients with hepatitis B and C, we sug-
gest monitoring viral replication during therapy and
treating hepatitis B patients with lamivudine if serum
HBV-DNA levels increase [104]. Prophylaxis with
lamivudine should be considered for every carrier
patient (HbsAg-positive) [104, 106].
Newly diagnosed neoplasia has occasionally been
reported in trials using infliximab in CD although the
possible role of infliximab in the pathogenesis of can-
cer is unclear [108]. However, in a recent multicentre
matched-pair study, the frequency of a new diagnosis
of neoplasia in CD patients treated with infliximab
was comparable with CD patients never receiving
infliximab [109]. In particular, the development of
lymphoma seemed not to be associated with inflix-
imab therapy but with immunosuppressive drugs,
particularly azathioprine, as previously reported
[110–115].
Infliximab is not indicated for patients with mod-
erate to severe congestive heart diseases [New York
Heart Association (NYHA) classification III–IV]
[116, 117]. Serum levels of TNF-α are elevated in
patients with heart failure and correlates with its
severity [118–121], but the use of infliximab (at a
dosage of 10 mg/kg) significantly increases mortality
and morbidity in patients with congestive heart fail-
ure [122]. Possible pathogenic mechanisms worsen-
ing congestive heart failure in infliximab-treated
patients are quite complicated and are reported in a
recent review [123].
Multiple sclerosis, demyelination and optic neuri-
tis associated with anti-TNF-α therapy are reported
[124–127], but a recent study shows that demyelinat-
ing disease occurs more commonly among patients
with IBD than among non-IBD patients [128]. Future
studies should clarify whether treatment with inflix-
imab results in further increased incidence of neuro-
logic diseases among IBD patients.
In pregnant women, drug safety has not been
Biological Approach in the Treatment of Crohn’s Disease 161
investigated, but some authors [129] found no differ-
ence in live birth and spontaneous abortion in an
infliximab-treated group compared with healthy
women. It is no clear if the drug is present in moth-
er’s milk. Patients who undergo infliximab therapy
should use a contraceptive method and, in the pres-
ence of a new pregnancy, biological therapy should
be stopped until the end of lactation.
Postsurgical Patients
Prophylactic therapy after resection for CD may pre-
vent recurrence of the disease. However, no clear
prophylactic drug regimens have been identified. In
the last decade, endoscopic recurrence has been con-
sidered a relevant outcome in patients suffering from
CD since they are strictly related to the clinical out-
come. After surgery, more than 70% of patients at 1
year and more than 85% at 3 years will have an endo-
scopic recurrence in the neoterminal ileum
[130–134]. Consequently, more than 20% of patients
will already have a clinical recurrence within the first
year after surgery, with a 10% increase in each subse-
quent year [135]. The pattern of CD remains
unchanged after surgery. Fistulising disease before
surgery will have the same complications after resec-
tion and early recurrent symptoms [131].
Standard therapy with steroids or 5-ASA formula-
tions are unable to prevent development of new
lesions at 1 year after resection whereas nitroimida-
zole antibiotics (metronidazole and ornidazole) seem
to be effective in preventing endoscopic and clinical
recurrences [136, 137]. However, some patients are
intolerant to nitroimidazole antibiotics. The benefit
of immunosuppression for preventing endoscopic
and clinical recurrence is lower than expected yet still
high (70% and more than 50%, respectively, at 1
year).
The role of biologic therapy in postsurgical
patients is still controversial, and no controlled trials
are present in literature. However, aggressive disease,
young age and intolerance to standard therapies
(steroid dependence; steroid-refractory or immuno-
suppressant side effects) may represent an indication
for infliximab therapy in the postsurgery period to
prevent disease recurrence, as recently suggested
[131].
New Drugs: What We Expect in the Near Future
Other Anti-TNF-Blocking Strategies
Adalimumab is a humanised immunoglobulin G
(IgG)1 monoclonal antibody directed against TNF-α
containing only human peptide sequences. It is indis-
tinguishable in structure and function from natural-
ly occurring human IgG1 antibodies. This molecule
binds soluble and membrane-bound TNF, fixes com-
plement and induces macrophage and T-cell apopto-
sis. The recently published CLinical assessment of
Adalimumab Safety and efficacy Studied as Induc-
tion therapy in Crohn’s (CLASSIC-I) study seems to
be superior to placebo for induction of remission in
patients with moderate to severe CD naïve to anti-
TNF therapy [138], confirming results of previous
open-labelled studies [139–143]. TNF-α exerts proin-
flammatory effects by binding to two specific trans-
membrane receptors, p55 and p75.
Etanercept is a human recombinant p75 recep-
tor/IgG fusion protein highly effective in rheumatoid
arthritis. Etanercept was shown to be ineffective in
patients with moderate to severe CD [144, 145] and at
the moment does not have marketing approval for
any indication in IBD. In vitro examination of T lym-
phocytes the lamina propria of patients with CD
seems to demonstrate that etanercept can neutralise
TNF-α but does not induce apoptosis of inflammato-
ry cells, differently from infliximab [146]. This exper-
imental evidence probably explains the differences in
efficacy between the two TNF-α-neutralising drugs.
However, efficacy of etanercept administration on
CD activity was assessed at 8 weeks [145]. Since the
biological effects of the drug begin after 4–8 weeks,
further clinical trials with a longer treatment period
are necessary to reach definitive results.
Onercept is a recombinant form of the human sol-
uble p55 TNF receptor, which neutralises the effect of
TNF-α. An open-labelled pilot study with onercept
suggests that this agent may be effective and well tol-
erated in patients with active CD [147]. However,
other randomised double-blind trials are necessary
to make definitive conclusions.
CDP571 is a humanised monoclonal IgG4 anti-
body anti-TNF-α (95% human, 5% murine). The first
study using a single dose of 5 mg/kg i.v. in a limited
number of patients reduced disease activity in CD at
2 weeks [148]. A successive study using a higher dose
of CDP571 (10 or 20 mg/kg) demonstrated a signifi-
cant clinical response in patients with moderate-to-
severe CD compared with placebo. In the same study,
retreatment with 10 mg/kg CDP571 at dose intervals
of 8 or 12 weeks seemed to be beneficial although not
statistically significant, probably due to the low num-
ber of patients with long-term treatment [149]. In a
later randomised double-blind placebo-controlled
study, patients with steroid refractory CD in clinical
remission were enrolled to verify corticosteroid spar-
ing at weeks 8 and 16. CD patients were treated with
a loading dose infusion (20 mg/kg) at week 0 fol-
lowed by a maintenance dose infusion (10 mg/kg) at
162 L. Frulloni, L. Bernardoni, C. Scattolini, I. Vantini
week 8 to ensure adequate plasma concentrations of
CDP571 throughout each 8-week dosing interval.
Corticosteroid sparing was achieved in a higher
number of patients treated with CDP571 than in
those treated with placebo at week 16 [150]. Repeat-
ed treatment (every 8 weeks up to 24 weeks) did not
seem to increase drug efficacy [151]. In conclusion,
CDP571 may provide an alternative option in
patients with previous hypersensitivity to infliximab
considering the very low risk for TBC or opportunis-
tic infections during CDP571 therapy.
Certolizumab pegol (CDP870) is a polyethylene
glycolated Fab’ fragment of a humanised anti-TNF-α
monoclonal antibody intended for subcutaneous
administration. A phase II dose-ranging trial,
enrolling patients with moderate to severe CD, was
recently published. Certolizumab at 4-week intervals
and dosage of 400 mg induces a rapid treatment
effect (2 weeks) and is clinically effective compared
with placebo [152]. Certolizumab was well tolerated
and, similarly to CDP571, gives potentially more
advantages in clinical practice compared with inflix-
imab. However, a phase III trial is needed to confirm
these results and to better understand the precise
role of this drug in the management of CD.
Thalidomide, an old drug recalled for the terato-
genic effects in pregnant women, has complex and
incompletely understood immunomodulatory prop-
erties. Multiple mechanisms of action have been
reported, particularly its ability to inhibit production
of TNF-α, inhibiting neoangiogenesis and shifting
immune response Th1 to Th2. Some recently pub-
lished papers seem to demonstrate that thalidomide
administered for 12 weeks is effective in patients with
steroid-resistant or steroid-refractory CD [153–157].
However, about 30% of patients withdrew from the
clinical studies due to the development of severe
adverse events. Preliminary reports also indicate that
thalidomide is effective as maintenance treatment
after induction of remission with infliximab [157].
Despite side effects (teratogenicity and peripheral
neuropathy) and adverse events, thalidomide may be
an alternative medical treatment in a select subgroup
of patients.
Anti-Inflammatory Cytokines
IL-10, discovered in 1989, has shown potent anti-
inflammatory properties in in vitro and in vivo ani-
mal studies. IL-10 exerts its anti-inflammatory effects
by down-regulating production of proinflammatory
cytokines by dendritic cells, macrophages and mono-
cytes. In clinical trials, a modest benefit was observed
in patients treated with subcutaneous injection of
humanised IL-10 [158-161]. In postsurgical CD
patients, IL-10 administration did not show any
effect [162]. The efficacy of IL-10 is lower than
expected, probably as a consequence of the stimula-
tion of INF-γ production [158]. Furthermore, serum
levels and tissue concentrations of IL-10 are general-
ly elevated in CD patients [5].
Recent experimental studies demonstrated that
the delivery of tissutal immunoregulatory proteins,
including IL-10, by gene therapy may be a potential-
ly exciting approach to treatment of IBD [163].
Future challenges for using gene therapy in CD will
be to establish safety, localisation and duration of the
expression of the transduced gene, as well as to
ensure that delivery of immunoregulatory proteins is
therapeutic.
IL-11 has been shown to be expressed and have
activity in multiple other tissues, including gut, but
to date, the physiologic role of this protein remains
unknown. Preliminary data on short-term treatment
with humanised IL-11 demonstrated that given sub-
cutaneously for 3 weeks (16 mg/kg per week), the
drug is well tolerated in patients with active CD [164].
A recent randomised trial reported that weekly sub-
cutaneous injection with rhIL-11 (15 mmg/kg per
week) compared with placebo is effective in inducing
remission in patients with active CD [165]. Potential-
ly, IL-11 may be an alternative or sparing agent for
corticosteroids in the management of CD, but its role
remains unclear.
Selective Inhibition of Adhesion Molecules
Adhesion molecules, up-regulated in inflamed CD
mucosa, play a role in the trafficking of leukocytes
and are involved in local lymphocyte stimulation and
antigen presentation. Integrins are heterodimeric
receptors consisting of an α4 subunit and either a β1
or β7 subunit (α4 β1 and α4 β7 integrins). Integrins
bind leukocytes in the vascular endothelium and
have a role in the migration of leukocytes across the
vascular endothelium. Therefore, they contribute to
recruitment, activation and survival of leukocytes
within the parenchyma. There is evidence that in
IBDs, integrins are overexpressed on the vascular
endothelium at the site of inflammation. In animal
models of colitis, antibodies against the a4 integrin
are able to significantly reduce gut inflammation
[166].
Recent double-blind placebo-controlled studies
using natalizumab, a humanised mouse monoclonal
antibody anti-a4 integrin (95% human, 5% murine),
in patients suffering from CD administrated at
dosage of 3 mg/kg per month twice improve clinical
remission and clinical response rates, as well as qual-
ity of life [167–169]. However, three cases of progres-
Biological Approach in the Treatment of Crohn’s Disease 163
sive multifocal leukoencephalopathy (PML), proba-
bly secondary to reactivation of latent JC poly-
omavirus infection, have been reported [170–172].
Retrospective analysis of serum samples showed that
JC virus became detectable only after three injections
of natalizumab monotherapy, and the serum viral
load increased by a factor of ten after two additional
injections. Although the large number of patients
enrolled in this clinical trial (over 3,000) and, conse-
quently, the low incidence of neurologic disease in
natalizumab-treated patients, the lack of diagnosis of
latent infection before natalizumab treatment limits,
due to ethical concerns, its clinical use [173]. In fact,
there is no specific treatment for PML at the moment.
A better understanding of the risk of PML in natal-
izumab-treated patients and the diagnostic possibili-
ties for a latent JC polyomavirus infection will define
the role of the drug in the treatment of CD.
Immunomodulators
Tacrolimus (FK506) is a macrolide antibiotic isolated
from Streptomyces tsukubaensis with greater
immunomodulatory properties than cyclosporine
and good oral absorption. Consequently, it has been
approved for the prophylaxis of organ rejection in
transplant patients. The proposed dosage in CD
patients is 0.1 mg/kg administered orally, adjusted
for each patient to reach a blood concentration range
between 5 and 15 ng/ml. Clinical open-labelled stud-
ies suggest the effectiveness and safety of short-term
and long-term oral tacrolimus therapy in patients
with perianal and enterocutaneous fistulising CD
[174–178]. However, side effects are numerous and
frequently reported by the patients. They include
gastrointestinal symptoms (abdominal pain, diar-
rhea, nausea), headache, insomnia, paresthesias,
tremor, temporary rise of creatinine, hyperkaliemia,
hypertension and opportunistic infections. There-
fore, tacrolimus may be an alternative drug in fis-
tulising CD if no success is achieved with conven-
tional therapy, including infliximab.
Mycophenolate mofetil (MMF) is an antimetabo-
lite that undergoes ester hydrolysis in mycophenolic
acid, its active form. Mycophenolic acid inhibits an
enzyme required for de novo guanosine nucleotide
biosynthesis and consequently blocks production of
necessary precursors for synthesis of DNA and RNA.
The action of MMF is considered to be directed in
particular against T and B lymphocytes, interfering
with the immune system. MMF has been used as an
immunosuppressant in the posttransplant patients
but also in chronic inflammatory diseases, particu-
larly in patients suffering from rheumatoid arthritis
and psoriasis, as with other drugs presented in this
review. Earlier studies showed a potential role of
MMF in CD patients intolerant to azathioprine that
was not confirmed in other studies [179–183]. How-
ever, a potential steroid-sparing effect has been sug-
gested. A recent open-labelled long-term-treatment
study in patients with complicated CD shows that
MMF at dosage of 1 g/b.i.d. induces an initial
response (at 6 months) in more than one half of the
patients, with a significant reduction in steroid
dosage. However, a large number of patients relapsed
during the long-term follow-up (median 18 months).
Furthermore, adverse events determined discontinu-
ation of treatment in 20% of long-term-treated
patients [184]. Therefore, we strongly believe that
MMF, similarly to other immunosuppressant, has a
possible therapeutic role in short-term treatment of
steroid-resistant or steroid-refractory CD patients
intolerant to azathioprine.
Helminths
Recent experimental and clinical evidence suggest
that helminthic parasites may be considered as a
therapeutic option in IBDs. CD is a result of an inap-
propriate immune response towards normal gut flora
and, probably, helminths down-regulate the host
immune response towards bacterial antigens. The
high prevalence of CD in industrialised Western
regions and the low incidence in developing coun-
tries may be related to the different incidence of
helminthic infestation. ‘‘IBD hygiene hypothesis’’ has
been formulated based on induction of the disease by
extremely hygienic environments in genetically pre-
disposed subjects. Data from experimental colitis
seems to show that helminths reduce inflammation,
probably counteracting the Th1-driven immune
response [185]. In fact, experimental colitis induced
in mice and rats with di- or trinitrobenzene sulfonic
acid (DNBS, TNBS), develop a Th1-cytokine-driven
colitis that shares features with CD [186, 187]. Expo-
sure to Schistosoma mansoni or Trichinella spiralis
attenuates DNBS-induced colitis and indicates a pro-
tective role of nematode infection in Th1-cell-driven
inflammation [188]. The authors suggested the possi-
bility of an immunological distraction with
helminths as a novel therapeutic strategy in CD.
Recently, therapy with Trichuris suis eggs in
patients suffering from CD has been postulated. The
life cycle of T. suis begins with the ingestion of
embryonated eggs. Embryonated eggs hatch in the
proximal small bowel, delivering larvae that migrate
aborally and attach to the mucosa of the distal small
bowel and proximal colon. After several weeks, they
mature and begin to spread eggs. T. suis ova are
capable of colonising a human host for several weeks
164 L. Frulloni, L. Bernardoni, C. Scattolini, I. Vantini
and are eliminated from the body without any specif-
ic therapy (self-limiting infection). In an preliminary
study, a single dose of 2,500 live T. suis eggs given
orally in patients suffering from active CD induced a
clinical response in all patients treated and a clinical
remission in the large part of cases [189]. Later, a
repeated dose of 2,500 live ova given orally every 3
weeks for 24 weeks induced a clinical response in
80% of patients and a clinical remission in 70% [190].
The positive results of these preliminary open-
labelled studies showed that helminth therapy is tol-
erated and effective in the treatment of CD.
Helminths inhibit intestinal inflammation by mecha-
nisms different from current medications, and the
efficacy of T. suis therapy supports the hypothesis
that helminthic exposure provides protection against
CD.
Probiotics
A possible pathogenesis of IBD includes mucosal
inflammation secondary to abnormal immune
response against resident bacteria. The intestinal
environment is a persisting stimulus in normal sub-
jects. In CD patients, normal intestinal bacteria in
genetically predisposed subjects or altered intestinal
flora may induce and amplify gut inflammation.
Therefore, manipulation of intestinal bacterial flora
is the rationale for the use of antibiotics. In the last
decade, probiotics (living micro-organisms with a
beneficial effect on the host), prebiotics (dietary
components that induce the growth of beneficial bac-
teria) and synbiotics (both the previous) have been
used in the treatment of CD. Despite the lack of ran-
domised clinical trials demonstrating efficacy of this
therapeutic approach to CD patients, a number of
review articles have been published during the last
years outlining its efficacy in the treatment of IBD
[191–193]. Based on experimental evidence, many
strains are tested for maintenance of remission in CD
patients.
Single-strain probiotics (Lactobacillus GG) at dif-
ferent dosages is not effective to maintain remission
in patients suffering from CD [194–196]. Probiotics
containing miscellaneous strains at high dosage may
be theoretically more effective than a single strain in
the treatment of CD, probably due to a synergic
effect. Recently, VSL#3, containing three strains of
Bifidobacterium (B. longum, B. infantis, B. breve),
four strains of Lactobacillus (L. acidophilus, L. casei,
L. delbrueckii, L. plantarum) and one strain of Strep-
tococcus salivarius subsp. thermophilus has been
proposed in the treatment of IBD. The postulated
pathogenic mechanism of VSL#3 is induction of tis-
sutal levels of the anti-inflammatory cytokine IL-10
and a greater expression of intestinal mucin, pre-
venting adhesion of pathological Escherichia coli
strains. Efficacy of VSL#3 is being tested in a double-
blind randomised trial for maintenance of remission
in recurrent chronic pouchitis.
Results of randomised double-blind clinical trials
are being awaited in order to make definitive conclu-
sions on the use of probiotics in CD patients.
Conclusions
The advent of biological therapy provides the oppor-
tunity to advance the care of patients with IBD
because we have opportunities to interrupt the dis-
ease pathophysiology in a more specific way. The
infliximab experience teaches that interfering with
cytokine-mediated inflammation improves the clini-
cal outcome of severe CD.
New biological drugs are coming in the near
future. Can we treat severe CD by blocking more than
one inflammatory mediator? The mechanism of
inflammation in cytokine-mediated CD is quite com-
plex. Cytokines are numerous, act at very low titre
(potent biological activity), have many target cells
and the cytokine response is mediated by specific cel-
lular receptors. Furthermore, different cytokines
produce the same effects, and large interactions
among cytokines are documented. We can postulate
that interfering with two or more cytokines may
improve the clinical course of CD. However, we do
not know yet if this approach may alter immune
defence towards pathogens and immune surveillance
on carcinogenesis, and we must consider that biolog-
ics are expensive drugs.
Biological drugs present a major challenge: the
more effective they are, the more side effects they can
produce. Therefore, biological therapy should care-
fully managed, with close observance for possible
adverse events and provision for any complication
resulting from treatment. Inappropriate manage-
ment of these potent drugs will compromise their use
in clinical practice.
Future clinical studies should address efficacy,
safety and cost effectiveness of biologic therapies for
CD and should provide the necessary information to
take maximum advantage of these new therapies.
References
1. Hanauer SB (2006) Inflammatory bowel disease: epi-
demiology, pathogenesis, and therapeutic opportuni-
ties. Inflamm Bowel Dis 12(Suppl 1):S3–S9
2. Gustot T, Lemmers A, Louis E et al (2005) Profile of
soluble cytokine receptors in Crohn's disease. Gut
54:488–495
Соседние файлы в папке Библиотека им академика М.И. Перельмана