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Silvio Danese, Stefano Semeraro,
Alfredo Papa, Italia Roberto, Franco Scaldaferri, Giuseppe Fedeli,
Giovanni Gasbarrini, Antonio Gasbarrini, Department of Internal
Medicine, Catholic University School of Medicine, L.go Vito 1, Rome 00168,
Italy
Supported by an unrestricted grant from Fondazione Ricerca
in Medicina
Correspondence to: Silvio Danese, MD, Department of
Internal Medicine, Catholic University School of Medicine, L.go Vito 1,
Rome 00168, Italy. sdanese@hotmail.com
Telephone:
-39-3392318230 Fax:
+39-06-97606741
Received: 2005-04-25
Accepted: 2005-06-18
Abstract
Inflammatory bowel
diseases (IBD) can be really considered to be systemic diseases since they
are often associated with extraintestinal manifestations, complications,
and other autoimmune disorders. Indeed, physicians who care for patients
with ulcerative colitis and Crohn�s disease, the two major forms of IBD,
face a new clinical challenge every day, worsened by the very frequent
rate of extraintestinal complications. The goal of this review is to
provide an overview and an update on the extraintestinal complications
occurring in IBD. Indeed, this paper highlights how virtually almost every
organ system can be involved, principally eyes, skin, joints, kidneys,
liver and biliary tracts, and vasculature (or vascular system) are the
most common sites of systemic IBD and their involvement is dependent on
different mechanisms.
� 2005 The WJG Press and Elsevier Inc. All
rights reserved.
Key words: Crohn's disease; Ulcerative
colitis; Inflammatory bowel disease
Danese S, Semeraro S, Papa A,
Roberto I, Scaldaferri F, Fedeli G, Gasbarrini G, Gasbarrini A.
Extraintestinal manifestations in inflammatory Bowel disease. World J
Gastroenterol 2005; 11(46): 7227-7236
http://www.wjgnet.com/1007-9327/11/7227.asp
INTRODUCTION
Inflammatory
bowel diseases (IBD) can be really considered to be systemic diseases
since they are often associated with extraintestinal manifestations,
complications, and other autoimmune disorders. Indeed, physicians who care
for patients with ulcerative colitis (UC) and Crohn�s disease (CD), the
two major forms of IBD, face a new clinical challenge every day, worsened
by the very frequent rate of extraintestinal complications. Virtually
almost every system can be involved, principally eyes, skin, joints,
kidneys, liver and biliary tracts, and vasculature (or vascular system)
are the most common sites of systemic IBD and their involvement is
dependent on different mechanisms.
Extraintestinal IBD-related immune disease can be classified into two
major groups: the first one includes reactive manifestations often
associated with intestinal inflammatory activity and therefore reflecting
a pathogenic mechanism common with intestinal disease (arthritis, erythema
nodosum, pyoderma gangrenosum, aphthous stomatitis,
iritis/uveitis)[1,2] (Table 1); the second one includes many
autoimmune diseases independent of the bowel disease that reflect only a
major susceptibility to autoimmunity. They are not considered (apart for
primary sclerosing cholangitis) as specific IBD features but only as
autoimmune associated diseases such as ankylosing spondilitis, primary
biliary cirrhosis, alopecia areata, and thyroid autoimmune disease and
others[1] (Table 2).
Table 1 Major
extraintestinal immune-related manifestations of IBD
Table 2
Autoimmune disorders associated to IBD
Moreover, many extraintestinal complications due to metabolic or
anatomical abnormalities caused directly by IBD have been reported
frequently and include osteoporosis, biliary and urinary lithiasis, and
anemia (Table 3).
Table 3
Extraintestinal complications in IBD and principal pathogenetic mechanisms
of arthritis
Aim of this
paper is to review the pathogenic mechanisms, frequency, features, and
therapy of the major IBD-associated extraintestinal
manifestations.
Pathogenesis of immune-related
extraintestinal manifestation in IBD
Extraintestinal
immune-related manifestations in IBD are directly dependent on intestinal
disease, often coexist in the same patients and have probably the same,
even if not completely clarified, pathogenesis[2]. Evidence
coming from many studies in genetically susceptible animal models of
colitis suggests the crucial role of enteric flora in activating the
immune system against bacterial antigens and contemporary against colonic
mucosa on the basis of an antigenic cross-reactivity (�antigen
mimicry�)[3]. The sharing of these colonic antigens by
extraintestinal organs, associated with a genetic susceptibility, would
finally lead to an immune attack to these organs[2]. One of the
best example is represented by primary sclerosing cholangitis occurring in
UC: in a subset of patients, the presence (in sera and colonic mucosa) of
anti-colonic mucosa auto-antibodies that cross react with biliary
epithelium has been identified[4]. Furthermore, recently a
colonic epithelial protein (CEP) and the human tropomyosin isoform 5
(hTM5), which are not only expressed in the colon but also in the biliary
tract, skin, eyes, and joints, have been suspected to be the major common
targets of autoimmune attack in extraintestinal organs of IBD patients
being IgG1 specific auto-antibodies identified in UC patients presenting
multiple extraintestinal manifestations[5].
It remains unclear why the extraintestinal
organs are not always involved at the same time and why these
auto-antibodies are absent in colonic CD. A partial explanation is that
genetic factors or local co-existent damage factors (infections, trauma)
could regulate the display of cryptic antigens and the susceptibility to
autoimmune attack[2].
According to
the previously explained mechanism, we can identify an immune induction
site, where T cells are primed, represented by the colon and the effectors
sites that are the extraintestinal organs. Immune cells infiltrate the
effectors sites (where they will proliferate) with the help of adhesion
molecules (α4β7 integrin, vascular adhesion protein 1) that have a
cytokine-mediated overexpression in specific tissues[6].
It is interesting how autoimmune attack
can happen many years after the removal of the colon. In the case of
primary sclerosing cholangitis (PSC), probably memory lymphocytes that
have been primed in the bowel can recirculate for many years also even
after the removal of the colon without causing damage until the occurrence
of a stimulus in the liver that activates inflammation with the
overexpression of adhesion molecules (MAdCAM and CCL 25) and consequent
persistent lymphocytes recruitment[7]. Interference with
adhesion molecules could be useful in the treatment of extraintestinal
manifestation as it has already been shown for the intestinal inflammatory
activity[8].
Genetic
susceptibility
Extraintestinal manifestations have certainly a
familial predisposition (83% of concordance between
siblings)[9] and this suggests the existence of a strong
genetic influence leading to the identification of many suspected
predisposal genes.
HLA system is considered as one of the major genetic
markers associated with IBD and extraintestinal manifestations, probably a
specific and appropriate antigen presentation that leads to autoimmune
reaction in particular predisposing
conditions.
It has been reported that UC
patients who display HLA-B8, DR3 phenotype have a 10-fold higher risk of
primary sclerosing cholangitis[10].
Moreover, UC patients who have HLA DRB1*0103
(DR103) have a higher risk of ocular and articular
manifestations[11] and patients with HLA-B*27 and B*58 have a
higher risk of uveitis (Orchard TR 2002). HLA-B*27 is strongly associated
with ankylosing spondylitis (AS) being present in 90% of these patients
but it seems not to be significantly associated with IBD; anyway IBD
patients with HLA-B*27 positiveness have a higher risk to develop AS and
IBD patients with axial articular involvement are HLA-B*27 positive from
25% to 75%[12]. The polymorphism -1031 C TNF-α has been
associated with erythema nodosum in IBD patients[13]. It is
possible that HLA genes interfere actively in the pathogenesis of
IBD-extraintestinal manifestations or that are in linkage disequilibrium
with other really responsible unknown genes. Moreover, caspase-activation
recruitment domain containing protein 15 (CARD15), a gene found in
association with ileocecal CD with a potential role in the bacterial
handling, has been recently associated with sacroiliitis even if previous
results did not agree[14].
Joint involvement in
IBD
Inflammatory arthropathies are the most common
extraintestinal manifestations in IBD patients with a prevalence ranging
between 7% and 25%[1,12]. Articular and musculoskeletal
manifestations are included in the spondyloarthropathies (SpAs) that are a
group of seronegative autoimmune related disorders with common
characteristics including: ankylosing spondylitis, reactive arthritis,
psoriatic arthritis, inflammatory bowel disease, some forms of juvenile
arthritis and acute anterior
uveitis[15].
Articular involvement
(peripheral or axial) can precede, be synchronous or begin afterward the
diagnosis of IBD, it is characteristically pauciarticular, asymmetrical,
transitory, migrating, prevalently non deforming. The axial involvement
can vary from asymptomatic sacroiliitis to inflammatory lower back pain to
ankylosing spondylitis (that occurs in 3% of IBD patients)[1].
It is interesting that the high incidence of
asymptomatic sacroiliitis (varying from 10% to 52%)[16,17,18]
and on the other hand the equally high incidence (about 50%) of
characteristic inflammatory low back pain in the absence of radiological
findings in IBD patients[12] indicating how history and
physical examination should be the diagnostic tools. Peripheral arthritis,
different from axial involvement, has a significant positive association
with the skin, mouth, and ocular manifestation; it happens more frequently
in CD (and particularly in colonic localization), often accompanies
intestinal activity ameliorating with IBD pharmacological or surgical
treatment[1]. In some patients, despite the amelioration of gut
inflammatory activity, articular disease
persists[19].
Arthritis is often
associated with enthesitis, tenosynovitis, dactylitis that can also appear
in the absence of arthritis[20]; typically they do not alter
inflammatory markers and can compromise deeply the quality of life.
Conventional treatment of inflamed joints include nonsteroidal
anti-inflammatory drugs and cyclooxygenase-2-inhibitor that should be used
for short-term period because of gastrointestinal side effect and IBD
reactivation risk[21,22] nevertheless at drug suspension
articular relapse can occur. Also local intra-articular steroid treatment
can be useful. The majority of interventional studies included
undifferentiated spondyloarthropathies- or ankylosing spondilytis patients
and no IBD patients, so that the results can only be extrapolated.
Sulfasalazine has been shown to be effective in peripheral joint disease
in SpAs patients[23,24] and positive but limited results have
been obtained with methotrexate[25]. Interesting results have
been obtained with anti TNF-α inhibitors in resistant SpAs with IBD. In
uncontrolled studies, infliximab has shown efficacy in the treatment of
SpAs in CD patients as induction and maintenance
therapy[26-28], also in the absence of acute phase reactants
and intestinal activity; there is also a reported case of positive results
in SpA associated with ulcerative
colitis[29].
In limited reports
(two cases) etanercept, that is ineffective in IBD
treatment[30], has given good results in the treatment of SpAs
associated to CD[31]. It is not clear at the moment the effect
of anti TNF-α therapies on articular damage evolution, certainly the early
recognition and appropriate treatment can help to limit the patient�s
inability.
Hepatobiliary disease
Hepatobiliary
diseases are common in IBD patients; they can or cannot be immuno-mediated
and can also depend on side effects of medications (see Table 4).
Elevation of liver function tests have been observed from 11% to 49% in
IBD patients in observational studies[32-34]. The most common
immuno-mediated hepatobiliary disease is primary sclerosing cholangitis
(PSC) that is a chronic cholestatic disorder characterized by inflammation
and fibrosis of the intrahepatic and extrahepatic bile ducts. It is more
frequent in male individuals, and the prevalence of IBD (mostly UC) in PSC
is about 70-80%[35]. Conversely about 2-7% of UC
patients[35,1] and 0.7-3.4% of MC patients have a diagnosis of
PSC[36,1]. Suggestive symptoms of PSC are fatigue, pruritus,
jaundice, and abdominal discomfort but it is not rare that the isolate
finding of abnormalities in liver biochemical markers (first of all
alkaline phosphatase); in fact 15-70% of PSC patients are
asymptomatic[37,1]. There are no specific auto-antibodies and
so biopsy or cholangiography is often necessary for the diagnosis. In PSC
patients, IBD frequently present some specific features: pancolonic
extension with rectal sparing, backwash ileitis, low intestinal activity,
and high pouchitis incidence after colectomy. These distinguishing
features have suggested the existence of an IBD-PSC specific clinical
phenotype[38]. It is well-known that the increased risk of
colonic dysplasia/carcinoma in PSC patients compared to the general
population (10-fold risk)[39] and to other UC
patients[35] it could depend on the long-lasting and
asymptomatic colitis (consequently often underestimated) and by
alterations in bile salts pool or folate deficiency. Similarly it has
significantly increased the risk of bile duct cancer[40] and
metabolic bone disease[41,38]. PSC has a median survival time
of 9-12 years from the time of diagnosis; it seems that neither
concomitant IBD presence nor colectomy (in UC patients) alter its natural
history. Moreover, the colorectal cancer risk does not seem to be
decreased after liver transplantation[42].
Table 4 Drugs
and their possible adverse side effects
The
therapeutic possibilities in PSC are limited; the best results have been
obtained with UDCA at a high dose (until 20 mg/kg)[43-45] and
the combined use of corticosteroids showed only a little additive
benefit[46,47].
The best clinical
approaches to PSC include colonoscopic examination with a biopsy to
identify a possible asymptomatic UC and/or cancer and a prevention
colonoscopy program in patients identified to have had UC. Association
between primary biliary cirrhosis (PBC) and UC is rare but possible and it
has been reported in 15 cases; similarly to the CSP it seems that
colectomy does not alter the progression of the hepatic
disease[48].
Apart from classical
immunological liver diseases in IBD patients, they are often observed for
other abnormalities. Liver enlargement is the most common reported finding
and is strictly related to steatosis grade. Steatosis has been described
in more than 30% of patients and it does not seem to be related to the
kind of IBD and sex. Data about the influence of disease activity and
pharmacological treatment on steatosis are
contradictory[49].
Also
cholelithiasis is more frequent in IBD patients (about 10%) than in the
general population (7%) and mainly in CD (first of all in ileal
localization); it seems to correlate with female sex, previous surgery
(mainly ileal resection), and old age. In limited series, it has been
shown to be less often symptomatic than in the general
population[49]. Probably cholelithiasis is caused by bile salt
pool alteration for malabsorption.
Rare complications reported in
literature are liver abscesses; it is thought that in most cases portal
bacteremia, favorite by mucosal barrier alterations, can be the principal
mechanism; rarely an ascending acute cholangitis in PSC has been suspected
to be the cause[50]. Portal vein thrombosis and suppurative
pylephlebitis has also been described in rare cases[49].
Cutaneous manifestations
Cutaneous manifestations
of IBD are relatively common. The incidence varies from about 10% at the
time of IBD diagnosis to more than 20% in the course of the
disease[1].
Skin lesions can be
classified into three principal classes: granulomatous, reactive, and
secondary to nutritional deficiency.
Granulomatous cutaneous lesions
have the same histological features of the bowel disease and include:
perianal and peristomal ulcers and fistulas, metastatic CD, oral
granulomatous ulcers.
Perianal disease is very frequent occurring in
about 50% of CD patients during their clinical history, and it varies from
perianal erythema to abscesses and perianal complex
fistulae[51].
Other fistulae can
be internal or entero-cutaneous; rarely develop on the abdominal scar of
laparotomy or at the umbilicus. Many efforts have been made to treat
fistulizing disease, and the classical surgical approach has been
supported recently by a larger use of drugs. Antibiotics,
azathioprine/mercaptopurine, tacrolimus, thalidomide showed efficacy in
uncontrolled studies[52] but at the moment only infliximab
showed effectiveness as induction[53] and maintenance
therapy[54] in phase III controlled trials; consequently it has
been approved as first line therapy in perianal and enterocutaneous
fistulizing CD by the United States Food and Drug Administration (FDA) and
the European Agency for the Evaluation of Medicinal Products in Europe.
Surgical procedures as colostomy in the more severe cases of perianal
fistulas, fistulotomy, abscesses drainage, and non-cutting setons
placement seem to be very useful, and the combined medical and surgical
approach is probably the best
one[55].
Metastatic CD is a rare
complication defined as the occurrence of specific granulomatous cutaneous
lesions remote from the intestinal disease[56]. It manifests as
subcutaneous nodules or ulcers mainly at the lower extremities with rare
case of genital (testicular and vulvar) localizations. It seems unrelated
to the bowel activity. Corticosteroids, antibiotics, azathioprine,
methotrexate[57], and more recently
infliximab[58,59] have been used successfully.
The group of
reactive skin manifestations of IBD includes aphthous stomatitis, erythema
nodosum, pyoderma gangrenosum, and the rare Sweet�s
syndrome.
Aphthous stomatitis is observed in
about 10% of patients: it occurs generally during active intestinal
disease, often recurs and shows a good response to intestinal treatment.
The prevalence of erythema nodosum in IBD is
3-8%. It appears more often in women, in the colonic localization, in
concomitance with arthritis and active intestinal disease[1];
furthermore, there is a positive response to
proctocolectomy[42].
Histological examination shows
lympho-histiocytic infiltrate of the lower derma. On the basis of
uncontrolled data, corticosteroids are generally an effective therapy;
also immunosuppressive therapy is used[56]. Resistant cases
have been treated effectively with
infliximab[60].
Pyoderma
gangrenosum is a very debilitating ulcerating chronic skin disorder
occurring in about 1-2% of IBD patients. It occurs often on the extensor
surface of the legs, particularly in coincidence with exacerbation of
intestinal disease and in association with other extraintestinal
manifestations (arthritis and erythema nodosum)[1,61].
Moreover, it is often associated with colonic involvement and in UC
patients it seems to benefit lesser than erythema nodosum from
colectomy[42].
According to disease severity, the treatment
(based on non-controlled evidence) can be local or systemic and includes a
high dose of oral or intralesional corticosteroids,
immunosuppressive/immunomodulatory therapy (cyclosporine, tacrolimus,
mycophenolate mofetil, azathioprine, dapsone)[61]. Infliximab
has shown to be very effective in the refractory disease and can be used
as first choice therapy[59,62,63]; also etanercept has been
reported to be effective in a refractory case of pyoderma
gangrenosum[64].
Another rare
cutaneous manifestation associated with IBD is the Sweet�s syndrome. It is
a neutrophilic dermatosis probably related to pyoderma gangrenosum
consistent with painful erythematous plaques or nodules often associated
with fever and leukocytosis that usually responds to
corticosteroids[65].
The more
frequent nutritional-deficient cutaneous manifestation is the
acrodermatitis enteropathica; it is caused by zinc deficiency and
manifests as a psoriasis form
erythema[61].
Furthermore, an
association between autoimmune cutaneous disease and IBD has been
reported. The most frequent disease is psoriasis (7-11% of IBD population
vs 1-2% of general population) than vitiligo and more rarely are
polimyositis, lupus erythematosus and scleroderma[66].
Ocular manifestations of IBD
Ocular
manifestations occur in about 10% of IBD patients. They can be
immune-related (episcleritis, scleritis, uveitis, corneal disease) or
related to drug exposure (cataract, glaucoma).
Episcleritis manifests as acute redness, irritation, burning, tender to
palpation; if there is also an impairment of vision, the presence of a
scleritis is possible. In this case, a referral to an ophthalmologist is
mandatory for risk of vision loss. Uveitis can be anterior and posterior
and is often associated with joints and skin manifestations. Anterior
uveitis is the most common and presents painful eye, visual blurring, and
photophobia but can be also asymptomatic and sometimes precedes the
diagnosis of IBD. Concomitance with IBD activity is typical for
episcleritis and uveitis[1,67].
Corneal disease (potential cause of perforation) has also been reported;
conjunctivitis is frequent in IBD population but probably does not differ
in frequency and etiologic factors from the general population. Anyway it
is important that the clinician is aware that serious ocular disease can
mimic conjunctivitis in IBD patients[67].
Ocular manifestations can benefit first of
all by the treatment of the underlying IBD (particularly for anterior
uveitis and episcleritis).
Treatment of ocular
disease can prevent complications such as retinal detachment or optic
nerve swelling in scleritis and secondary glaucoma and cataracts in
uveitis.
Cycloplegics, NSAIDs, topical and
systemic steroids are useful. Immunosuppression can be necessary in case
of scleritis; sulfasalazine/mesalazine seems to prevent anterior uveitis
recurrence[67]. Recently infliximab has shown efficacy in acute
uveitis, in episcleritis, and scleritis[68,69]. Other rare
reported ocular manifestations of IBD are: retinitis, orbital IBD, retinal
arterial and venal occlusion, optic neuritis, retinal vasculitis, marginal
corneal disease, lid margin
ulcers[70,67].
Metabolic osteopathy
IBD
is also associated with an increased risk of osteoporosis and osteopenia.
The prevalence rates ranges from 2% to 30% for osteoporosis and from 40%
to 50% for osteopenia[71]. The risk of fractures in IBD
patients varies widely in different studies[72-74] (from an OR
of 1.41 to 2.5) the real impact being completely clear on the IBD
population; because of contrasting results, it is also uncertain if the
risk is comparable for UC and MC and for men and women.
Osteoporosis occurrence is often
underestimated as shown in an observational study conducted in the
UK[74] in which women aged 65 years with severe IBD have shown
a 10-years probability of hip fracture of 7%; nevertheless only 13% of
patients who had already sustained a fracture were in bone-sparing
therapy.
Furthermore, a significant number of
fractures in IBD patients (as in the general osteoporotic population) are
asymptomatic (14.2% in a study of Stockbrugger) and many fractures will be
underreported[75].
Bone loss and
consequent fractures are certainly multifactorial processes. They are
significantly dependent on the age (above 60 years), the use of
corticosteroids[74-76] and the grade of systemic inflammation
(intestinal disease activity correlates with the risk of
fracture)[74].
Recently the role of
the inflammatory-induced osteopenia has been revaluated and a surface
receptor (RANK) localized on osteoclasts that induces osteoclastogenesis
has been identified. Its ligand (RANKL) is induced by proinflammatory
cytokines; its decoy receptor that prevents ligation of RANKL to RANK is
called osteoprotegerin (OPG), and is produced by osteoblasts and prevents
bone loss. Its production is inhibited by corticosteroids and increased by
bisphosphonates. So OPG-RANKL-RANK system is certainly a pivot in
inflammatory-induced bone loss[77,78]. Initial therapeutical
use of recombinant OPG in inflammation-induced osteoporosis seems to be
promising[79].
On the basis of
these findings, the role of nutritional deficiency could be smaller than
previously thought, as also shown in a preliminary recent observational
study that found low intake of calcium (<1 000 mg/die) and vitamin D
(<200 IU/die) in premenopausal IBD women not to be a predictor of bone
loss[80].
Other factors that could
favor osteoporosis are the use of corticosteroids, the hypogonadism, and
the immobility. Also genetic markers have been proposed as determinants of
bone loss in IBD patients. In the future, they could contribute to
identify high-risk patients and support clinical behavior[81].
Definition of a correct clinical approach is
difficult because therapeutic trials on IBD patients with the specific
end-point of fractures prevention are lacking and an extrapolation by the
major clinical trials on osteoporosis is difficult, since these studies
involve postmenopausal patients, certainly older than IBD patients with
osteoporosis.
A small randomized,
placebo-controlled trial showed that alendronate significantly ameliorates
spine bone density compared with the control group after 1-year-long
therapy in IBD patients[82]. Also azathioprine, effective on
intestinal activity, seems to have positive effect on bone loss
retardation[83].
The expert
recommendations on therapy, in the absence of more specific evidence, do
not significantly differ from that of the general population.
Supplementation of vitamin D for patients above 60 years, therapy with
bisphosphonates in case of osteoporosis (identified with densitometry),
osteoporotic fractures and chronically steroid treatment, use of minimum
dosage of corticosteroids (preferentially non-systemic), correction of
early menopause or male hypogonadism by hormone therapy have also been
reported[84,85]. Recently apart from OPG use, another
osteoanabolic substance, the parathyroid hormone 1-34, is under evaluation
for the steroid-induced osteoporosis[86]; in the future they
could show effectiveness in IBD osteoporosis. More efforts are yet to be
taken in the identification of high-risk patients and in the definition of
the most cost-effective clinical behavior in IBD patients.
Thromboembolism and IBD
Patients with IBD have a
well-known increased risk (threefold higher than in controls) of
thromboembolism (TE), which is an important cause of morbidity and
mortality. The incidence ranges from 1.2% to 6.1% according to different
studies and in necropsy studies it reaches 39%[87].
Thrombosis accidents occur prevalently as
deep vein thrombosis and pulmonary thromboembolism; they happen in earlier
age than in non-IBD patients and are more frequent in active or
complicated IBD; the type of IBD and the sex seems not to influence
thromboembolic risk[87,88]. Using the logistic regression
model, it has been found that IBD is an independent risk factor for
thrombosis that is a specific IBD feature. In fact, other inflammatory
chronic condition as rheumatoid arthritis or chronic intestinal
malabsorptive conditions as celiac disease do not show an increased risk
of TE[87].
IBD patients have a frequent exposure to
classical thrombosis risk factors: immobility, surgery, steroid therapy,
central venous catheter, contraceptives/hormone substitution, smoke;
nevertheless, these risk factors do not explain the TE risk increase
completely[87].
It is well-known
that in IBD patients there is not a completely explained imbalance between
coagulation and fibrinolysis in favor of
coagulation.
Active intestinal inflammation is
not probably the unique risk determinant since about
30-40%[87,89] of thrombosis occurs during quiescence of the IBD
and proctocolectomy has not shown a very clear protective effect on
recurrent venous thrombosis[90].
Also other factors have been claimed; hyperhomocysteinemia, a well-known
risk factor for venous and arterial thrombosis, occurs more often in IBD
patients than in the general population and seems to be directly dependent
by folate and vitamin B12 deficiency even if there is not a complete
concordance in literature[91-93].
The role of the inherited thrombophilia has been recently
reviewed[94]. The analysis has shown that the most frequent
prothrombotic genetic mutations (factor V Leiden mutation, G20210A
mutation in the gene of prothrombin, homozygous in the gene of
methylenetetrahydrofolate reductase) are not significantly associated with
IBD.
At the same time with the limit of a small number of subjects
participating in the studies, it seems that there is no difference in the
prevalence of genetic mutations in IBD patients with thrombosis compared
with non-IBD subjects with thrombosis. Anyway a recent study comparing IBD
patients with thrombosis and IBD controls has revaluated the role of
genetic factors finding a significant higher prevalence of factor V Leiden
in the thrombosis group (20% vs 0%)[95].
The data regarding the prevalence of
antiphospholipid antibodies in IBD are conflicting, but seem to suggest an
increase frequency in IBD. In limited series, the level of lipoprotein (A)
has been found to be higher than in controls[87]. No evidence
exists about treating thrombotic events differently than in non-IBD
patients[87].
Conclusively many
factors are suspected to play a role in the thromboembolic increased risk
of IBD patients but further studies are necessary to identify their
specific contribution.
At the moment in IBD
patients the elimination of removable risk factors is recommendable; in
case of thrombosis probably is useful to evaluate the thrombotic risk
performing coagulation laboratory parameters and genetic tests.
Anemia
Anemia is a frequent extraintestinal
manifestation in IBD; about one-third of IBD patients have hemoglobin
levels below 12 g/dL[96]. The anemic state correlates strictly
with the quality of life and so is certainly an important problem in the
therapeutic management of chronic patients[97]. Multiple
pathogenic mechanisms often coexist in anemic patients leading to mixed
features anemia. Chronic intestinal bleeding with iron loss (due to bowel
inflammation) causes a hypochromic and microcytic anemia with associated
hypoferremia and hypoferritinemia; the chronic inflammatory disease
(typically characterized by hyperferritinemia) can cause anemia through
the proinflammatory cytokine-dependent diversion of iron traffic to
reticuloendothelial system and erythroid progenitor cell development
interference[98]. The same inflammatory cytokines are able to
inhibit erythropoietin production[99]. Recently, in vitro
anti-TNF-α factors showed positive effects in preventing apoptosis of
erythroid cells[100]. Other mechanisms implied in anemia are
iron malabsorption (in duodenum or upper jejunum disease CD), vitamin B12
malabsorption (in terminal ileum and gastric CD), and folate deficiency
(malabsorption, inadequate diet, and side effects of sulfasalazine and
methotrexate). Vitamin B12 and folate deficient anemia is
characteristically macrocytic. Myelosuppressive direct effects have been
reported frequently for azathioprine/6-mercaptopurine and sometimes also
for sulfasalazine and 5-aminosalycilic acid[101]. Correction of
the anemic state is useful also in low-grade anemia. It is important to
prevent and treat intestinal flares that are often the cause of anemia and
to reintegrate the lacking of iron, B12, and folate.
In low-ferritin patients, prevention therapy
with oral iron can be sufficient; in overt anemia iron intravenous
(preferentially iron sucrose) supplementation should be preferred to oral
route because of major efficacy and no collateral intestinal side effect.
Epo therapy is useful in patients with no satisfactory response to iron
therapy alone[101]. Low levels of Epo, soluble transferring
receptors or transferrin have shown to predict iron sucrose
resistance[102].
Urinary system
manifestations
IBD is a risk factor for renal immune and
non-immune mediated diseases.
The prevalence
of nephrolithiasis in IBD varies from 2% to 6% and is more frequent in CD
than in UC[103]. Calcium-oxalate stones are the most common and
are caused by hyperoxaluria due to increased intestinal absorption of
oxalate. In fact in the bowel that does not absorb fatty acids link
calcium preventing calcium-oxalate precipitation with the consequent
increased absorbable oxalate fraction. More than one lithogenic factors
are often present in the same patient, more frequently during active
disease. The main lithogenic risk factors are: low urinary volume, low
urinary PH, increased excretion of lithogenic substances as oxalate,
phosphate, uric acid, and decreased concentration of anti-lithogenic
substances as citrate and magnesium. Colectomy in UC and ileo-colonic
resection in CD seems to further increase the risk of lithiasis and
oxalate stone formation occurs mainly in ileal CD[104].
Periodic sonographic examination is
recommended for early diagnosis and for the prevention of complications.
Furthermore, minimal signs of tubular damage have been found in about 20%
of IBD patients but rarely they are clinically relevant[105].
A calculus uretheral obstruction, prevalently
localized on the right, is also possible and is related to the mechanisms
of adherence and compression by inflamed bowel (prevalently terminal
ileum)[103]. Urinary tract fistulas occur in about 1.7-7.7% of
patients. They can cause pneumaturia, dysuria, recurrent infections, and
fecaluria. At the moment in most cases, the non-satisfactory response to
medical therapy makes surgery the best option[106].
Clinical relevant renal amyloidosis has been
reported in about 1% of IBD patients (more frequently in ileal CD). It is
probably related to acute phase reaction proteins[107]. In IBD
patients, cases of glomerulonephritis causing nephrotic syndrome and renal
failure have also been reported. They are related to intestinal disease
activity, are quite responsive to IBD therapy and can present many
patterns at histology[108]. Moreover, it seems that mi nimal,
clinically non significant, glomerular inflammatory changes are quite
frequent in IBD patients as shown in a post mortem study (70% of subtle
renal lesions vs 8% of controls)[109] but following data do not
exploit this aspect.
Other rare extraintestinal
manifestations
It has been reported in literature about the
occurrence of other rare extraintestinal manifestations of IBD, such as,
chronic recurrent multifocal osteomyelitis (CRMO),
myositis[110], polyneuropathy, Guillain-Barre
syndrome[111], lymphocytic
encephalomyeloneuritis[112], myocarditis[113], and
pleuropericarditis[114].
Drug-induced side
effects
Many drugs used in IBD treatment can cause side effects
involving various organs (Table 4). These effects that often need drug
interruption enter in differential diagnosis with extraintestinal
manifestations/complications of IBD; their early diagnosis is facilitated
by periodical serum analysis exploring liver, pancreatic, renal, and
hematological system integrity as for example is recommended in
methotrexate and azathioprine use[115]. Furthermore, the
limited use to short period of other drugs can prevent their effect as for
example as it often happens for corticosteroids (Table 4).
CONCLUSION
IBD is a
systemic disease, since its clinical manifestations can affect not only
the bowel but also practically any other organ (eyes, liver,
osteoarticular system, kidneys, and so on) through different (often not
completely cleared) mechanisms. At the moment, awareness of the high
incidence of extraintestinal manifestations is often inadequate.
Therefore, prevention, early diagnosis, and adequate treatment of these
pathological conditions, sometimes more dramatic than the intestinal
disease, are necessary to increase patients� health. Clinical
interventional trials in IBD patients should consider these conditions
with more attention to indicate the best cost-effective method for
clinicians.
REFERENCES
1
Veloso FT, Carvalho J, Magro F. Immune-related systemic
manifestations of inflammatory bowel disease. A prospective
study of 792 patients. J Clin
Gastroenterol 1996; 23: 29-34
2
Das KM. Relationship of extraintestinal involvements in
inflammatory bowel disease: new insights into autoimmune
pathogenesis. Dig Dis Sci 1999; 44: 1-13
3
Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M,
Fernandez-Sueiro JL, Balish E, Hammer RE. The germfree
state prevents development of gut
and joint inflammatory disease in HLA-B27 transgenic rats. J Exp
Med 1994; 180:
2359-2364
4
Chapman RW, Cottone M, Selby WS, Shepherd HA, Sherlock S, Jewell
DP. Serum autoantibodies, ulcerative colitis and
primary sclerosing cholangitis.
Gut 1986; 27: 86-91
5
Geng X, Biancone L, Dai HH, Lin JJ, Yoshizaki N, Dasgupta A,
Pallone F, Das KM. Tropomyosin isoforms in intestinal
mucosa: production of
autoantibodies to tropomyosin isoforms in ulcerative colitis.
Gastroenterology 1998; 114: 912-922
6
Salmi M, Alanen K, Grenman S, Briskin M, Butcher EC, Jalkanen S.
Immune cell trafficking in uterus and early life is
dominated by the mucosal
addressin MAdCAM-1 in humans. Gastroenterology 2001; 121:
853-864
7
Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hubscher SG,
Briskin M, Salmon M, Adams DH. Hepatic endothelial
CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the
liver in primary sclerosing cholangitis. J Exp
Med 2004; 200: 1511-1517
8 Rutgeers P. ColombelJ, Enns R, et al.
Subanalyses from a phase 3 study on the evaluation of natalizumab in
active
Crohn�s disease
therapy-1(ENACT-1). Gut 2003; 52: A239
9
Satsangi J, Grootscholten C, Holt H, Jewell DP Clinical patterns of
familial inflammatory bowel disease. Gut 1996; 38:
738-741
10
Chapman RW, Varghese Z, Gaul R, Patel G, Kokinon N, Sherlock S.
Association of primary sclerosing cholangitis with
HLA-B8. Gut 1983;
24: 38-41
11
Roussomoustakaki M, Satsangi J, Welsh K, Louis E, Fanning G, Targan
S, Landers C, Jewell DP. Genetic markers may
predict disease behavior in
patients with ulcerative colitis. Gastroenterology 1997;
112:1845-1853
12
De Vos M. Review article: joint involvement in inflammatory bowel
disease. Aliment Pharmacol Ther 2004; 20: 36-42
13
Orchard TR, Chua CN, Ahmad T, Cheng H, Welsh KI, Jewell DP. Uveitis
and erythema nodosum in inflammatory bowel
disease: clinical features and the role of HLA genes.
Gastroenterology 2002; 123: 714-718
14
Peeters H, Vander Cruyssen B, Laukens D, Coucke P, Marichal D, Van
Den Berghe M, Cuvelier C, Remaut E, Mielants H,
De Keyser F, Vos MD. Radiological sacroiliitis, a hallmark of spondylitis,
is linked with CARD15 gene polymorphisms in
patients with Crohn's disease. Ann Rheum Dis 2004; 63:
1131-1134
15
Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin
A, Cats A, Dijkmans B, Olivieri I, Pasero G.The
European Spondylarthropathy Study
Group preliminary criteria for the classification of spondylarthropathy.
Arthritis Rheum
1991; 34: 1218-1227
16 Dekker-Saeys BJ,
Meuwissen SG, Van Den Berg-Loonen EM, De Haas WH, Agenant D, Tytgat GN.
Ankylosing spondylitis
and inflammatory bowel disease. Prevalence of peripheral arthritis,
sacroiliitis, and ankylosing spondylitis in patients
suffering from inflammatory bowel disease. Ann Rheum Dis 1978;
37: 33-35
17
de Vlam K, Van de Wiele C, Mielants H, Dierckx RA, Veys EM. Is
99mTc human immunoglobulin G scintigraphy (HIG-scan
useful for the detection of spinal inflammation in ankylosing spondylitis?
Clin Exp Rheumatol 2000; 18: 379-382
18
Davis P, Thomson AB, Lentle BC. Quantitative sacroiliac
scintigraphy in patients with Crohn's disease. Arthritis Rheum
1978; 21: 234-237
19
Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in
inflammatory bowel disease: their articular
distribution and natural history.
Gut 1998; 42: 387-391
20
Salvarani C, Fornaciari G, Beltrami M, Macchioni PL.
Musculoskeletal manifestations in inflammatory bowel disease. Eur J
Intern Med 2000; 11: 210-214
21
Felder JB, Korelitz BI, Rajapakse R, Schwarz S, Horatagis AP, Gleim
G. Effects of nonsteroidal antiinflammatory drugs on
inflammatory bowel disease: a case-control study. Am J
Gastroenterol 2000; 95: 1949-54
22
Mahadevan U, Loftus EV Jr, Tremaine WJ, Sandborn WJ. Safety of
selective cyclooxygenase-2 inhibitors in
inflammatory bowel
disease. Am J Gastroenterol 2002; 97: 910-914
23
Clegg DO, Reda DJ, Weisman MH, Cush JJ, Vasey FB, Schumacher HR Jr,
Budiman-Mak E, Balestra DJ, Blackburn WD,
Cannon GW, Inman RD, Alepa FP,
Mejias E, Cohen MR, Makkena R, Mahowald ML, Higashida J, Silverman SL,
Parhami N,
Buxbaum J, Haakenson
CM, Ward RH, Manaster BJ, Anderson RJ, Henderson WG. Comparison of
sulfasalazine and
placebo in the
treatment of reactive arthritis (Reiter's syndrome). A Department of
Veterans Affairs Cooperative Study.
Arthritis Rheum
1996; 39: 2021-2027
24
Dougados M, vam der Linden S, Leirisalo-Repo M, Huitfeldt B, Juhlin
R, Veys E, Zeidler H, Kvien TK, Olivieri I, Dijkmans
B. Sulfasalazine in the treatment
of spondylarthropathy. A randomized, multicenter, double-blind,
placebo-controlled
study.
Arthritis Rheum 1995; 38: 618-627
25
Altan L, Bingol U, Karakoc Y, Aydiner S, Yurtkuran M, Yurtkuran M.
Clinical investigation of methotrexate in the treatment
of ankylosing spondylitis. Scand J Rheumatol 2001; 30:
255-259
26
Generini S, Giacomelli R, Fedi R, Fulminis A, Pignone A, Frieri G,
Del Rosso A, Viscido A, Galletti B, Fazzi M, Tonelli F,
Matucci-Cerinic M. Infliximab in spondyloarthropathy associated with
Crohn's disease: an open study on the efficacy of
inducing and maintaining remission of musculoskeletal and gut
manifestations. Ann Rheum Dis 2004; 63: 1664-1669
27
Van den Bosch F, Kruithof E, De Vos M, De Keyser F, Mielants H.
Crohn's disease associated with spondyloarthropathy:
effect of TNF-alpha blockade with infliximab on articular symptoms.
Lancet 2000; 356: 1821-1822
28
Herfarth H, Obermeier F, Andus T, Rogler G, Nikolaus S, Kuehbacher
T, Schreiber S. Improvement of arthritis and
arthralgia after treatment with
infliximab (Remicade) in a German prospective, open-label, multicenter
trial in refractory
Crohn's disease. Am J Gastroenterol 2002; 97:
2688-2690
29
Gamian A, Romanowska A, Romanowska E. Immunochemical studies on
sialic acid-containing lipopolysaccharides from
enterobacterial species. FEMS
Microbiol Immunol 1992; 4: 323-328
30
Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD,
Tremaine WJ, Johnson T, Diehl NN, Zinsmeister AR.
Etanercept for active Crohn's disease: a randomized, double-blind,
placebo-controlled trial. Gastroenterology 2001; 121:
1088-1094
31
Marzo-Ortega H, McGonagle D, Emery P. Etanercept treatment in
resistant spondyloarthropathy: imaging, duration of
effect and efficacy on reintroduction. Clin Exp Rheumatol 2002;
20: S175-177
32
Broome U, Hauzenberger D, Klominek J. Adhesion molecules in primary
biliary cirrhosis and primary sclerosing
cholangitis. Hepatogastroenterology 1996; 43:
1109-1112
33
Okolicsanyi L, Fabris L, Viaggi S, Carulli N, Podda M, Ricci G.
Primary sclerosing cholangitis: clinical presentation, natural
history and prognostic variables: an Italian multicentre study. The
Italian PSC Study Group. Eur J Gastroenterol Hepatol
1996; 8: 685-691
34
Talwalkar JA, Lindor KD. Primary sclerosing cholangitis. Inflamm
Bowel Dis 2005; 11: 62-72
35
Loftus EV Jr, Sandborn WJ, Tremaine WJ, Mahoney DW, Zinsmeister AR,
Offord KP, Melton LJ 3rd. Risk of colorectal
neoplasia in patients with primary
sclerosing cholangitis. Gastroenterology 1996; 110:
432-440
36
Rasmussen HH, Fallingborg JF, Mortensen PB, Vyberg M, Tage-Jensen
U, Rasmussen SN. Hepatobiliary dysfunction and
primary
sclerosing cholangitis in patients with Crohn's disease. Scand J
Gastroenterol 1997; 32: 604-610
37
Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL, Hunter
EB, Fleming TR, Fisher LD, Beaver SJ, LaRusso
NF.
Primary sclerosing cholangitis: natural history, prognostic factors and
survival analysis. Hepatology 1989; 10: 430-436
38
Loftus EV Jr, Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS,
Zinsmeister AR, Jewell DA, Sandborn WJ. PSC-IBD:
a
unique form of inflammatory bowel disease associated with primary
sclerosing cholangitis. Gut 2005; 54: 91-96
39
Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Loof L, Danielsson A,
Hultcrantz R, Lindgren S, Prytz H, Sandberg-Gertzen
H, Almer S, Granath F, Broome U.
Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.
J Hepatol 2002;
36: 321-327
40
Boberg KM, Bergquist A, Mitchell S, Pares A, Rosina F, Broome U,
Chapman R, Fausa O, Egeland T, Rocca G, Schrumpf
E. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and
clinical presentation. Scand J Gastroenterol
2002; 37: 1205-1211
41
Angulo P, Therneau TM, Jorgensen A, DeSotel CK, Egan KS, Dickson
ER, Hay JE, Lindor KD. Bone disease in patients with
primary sclerosing cholangitis:
prevalence, severity and prediction of progression. J Hepatol
1998; 29: 729-735
42
Goudet P, Dozois RR, Kelly KA, Ilstrup DM, Phillips SF.
Characteristics and evolution of extraintestinal manifestations
associated with ulcerative
colitis after proctocolectomy. Dig Surg 2001; 18:
51-55
43
Harnois DM, Angulo P, Jorgensen RA, Larusso NF, Lindor KD.
High-dose ursodeoxycholic acid as a therapy for patients
with primary sclerosing
cholangitis. Am J Gastroenterol 2001; 96: 1558-1562
44
Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman
RW. A preliminary trial of high-dose
ursodeoxycholic acid in primary
sclerosing cholangitis. Gastroenterology 2001; 121:
900-907
45
Rost D, Rudolph G, Kloeters-Plachky P, Stiehl A. Effect of
high-dose ursodeoxycholic acid on its biliary enrichment in
primary sclerosing cholangitis.
Hepatology 2004; 40: 693-698
46
Boberg KM, Egeland T, Schrumpf E. Long-term effect of
corticosteroid treatment in primary sclerosing cholangitis
patients. Scand J
Gastroenterol 2003; 38: 991-995
47
van Hoogstraten HJ, Vleggaar FP, Boland GJ, van Steenbergen W,
Griffioen P, Hop WC, van Hattum J, van Berge
Henegouwen GP, Schalm SW, van Buuren HR. Budesonide or prednisone in
combination with ursodeoxycholic acid in
primary sclerosing cholangitis: a
randomized double-blind pilot study. Belgian-Dutch PSC Study Group. Am
J Gastroenterol
2000;
95: 2015-2022
48
Ohge H, Takesue Y, Yokoyama T, Hiyama E, Murakami Y, Imamura Y,
Shimamoto F, Matsuura Y Progression of primary
biliary cirrhosis after
proctocolectomy for ulcerative colitis. J Gastroenterol 2000;
35: 870-2
49
Bargiggia S, Maconi G, Elli M, Molteni P, Ardizzone S, Parente F,
Todaro I, Greco S, Manzionna G, Porro GB.
Sonographic prevalence of liver steatosis and biliary tract stones in
patients with inflammatory bowel disease: study of
511 subjects at a single center. J Clin Gastroenterol 2003;
36: 417-420
50
Margalit M, Elinav H, Ilan Y, Shalit M. Liver abscess in
inflammatory bowel disease: report of two cases and review of
the literature. J
Gastroenterol Hepatol 2004; 19: 1338-1342
51
Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS,
Zinsmeister AR, Sandborn WJ. The natural
history of fistulizing Crohn's disease in Olmsted County, Minnesota.
Gastroenterology 2002; 122: 875-880
52
Sandborn WJ. Evidence-based treatment algorithm for mild to
moderate Crohn's disease. Am J Gastroenterol 2003;
98: S1-5
53
Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S,
Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao
W, Rutgeerts P. Maintenance
infliximab for Crohn's disease: the ACCENT I randomised trial.
Lancet 2002; 359:
1541-
1549
54
Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak
RN, Kamm MA, Korzenik JR, Lashner BA, Onken
JE, Rachmilewitz D, Rutgeerts P,
Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ.
Infliximab
maintenance therapy
for fistulizing Crohn's disease. N Engl J Med 2004; 350:
876-885
55
Regueiro M, Mardini H. Treatment of perianal fistulizing Crohn's
disease with infliximab alone or as an adjunct to exam
under anesthesia with seton placement. Inflamm Bowel Dis 2003;
9: 98-103
56
Tavarela Veloso F. Review article: skin complications associated
with inflammatory bowel disease. Aliment Pharmacol
Ther 2004; 20
Suppl 4: 50-53
57
Guest GD, Fink RL. Metastatic Crohn's disease: case report of an
unusual variant and review of the literature. Dis Colon
Rectum 2000;
43: 1764-1766
58
Konrad A, Seibold F. Response of cutaneous Crohn's disease to
infliximab and methotrexate. Dig Liver Dis 2003; 35:
351-6
59
Kugathasan S, Miranda A, Nocton J, Drolet BA, Raasch C, Binion DG
Dermatologic manifestations of Crohn disease in
children: response to infliximab.
J Pediatr Gastroenterol Nutr 2003; 37: 150-154
60
Kaufman I, Caspi D, Yeshurun D, Dotan I, Yaron M, Elkayam O. The
effect of infliximab on extraintestinal manifestations
of Crohn's disease. Rheumatol Int 2005; 25: 406-410
61
Menachem Y, Gotsman I. Clinical manifestations of pyoderma
gangrenosum associated with inflammatory bowel
disease. Isr Med Assoc J 2004; 6: 88-90
62
Regueiro M, Valentine J, Plevy S, Fleisher MR, Lichtenstein GR.
Infliximab for treatment of pyoderma gangrenosum
associated with inflammatory bowel disease. Am J Gastroenterol
2003; 98: 1821-1826
63
Gupta AK, Skinner AR. A review of the use of infliximab to manage
cutaneous dermatoses. J Cutan Med Surg 2004; 8:
77-89
64
McGowan JW 4th, Johnson CA, Lynn A. Treatment of pyoderma
gangrenosum with etanercept. J Drugs Dermatol 2004;
3: 441-444
65
Gibson LE. Sweet syndrome. Mayo Clin Proc 2005; 80:
549
66
Hoffmann RM, Kruis W. Rare extraintestinal manifestations of
inflammatory bowel disease. Inflamm Bowel Dis 2004;
10: 140-147
67
Mintz R, Feller ER, Bahr RL, Shah SA. Ocular manifestations of
inflammatory bowel disease. Inflamm Bowel Dis 2004;
10: 135-139
68
Diaz-Valle D, Miguelez Sanchez R, Fernandez Espartero MC, Pascual
Allen D. Treatment of refractory anterior diffuse
scleritis with infliximab.
Arch Soc Esp Oftalmol 2004; 79: 405-408
69
Fries W, Giofre MR, Catanoso M, Lo Gullo R. Treatment of acute
uveitis associated with Crohn's disease and sacroileitis
with infliximab. Am J Gastroenterol 2002; 97: 499-500
70
DiSilvestro RA, Greenson JK, Liao Z. Effects of low copper intake
on dimethylhydrazine-induced colon cancer in rats.
Proc Soc Exp Biol Med 1992; 201: 94-97
71
Papaioannou A, Giangregorio L, Kvern B, Boulos P, Ioannidis G,
Adachi JD. The osteoporosis care gap in Canada. BMC
Musculoskelet Disord
2004; 5: 11
72
Bernstein CN, Blanchard JF, Leslie W, Wajda A, Yu BN. The incidence
of fracture among patients with inflammatory
bowel disease. A population-based cohort study. Ann Intern Med
2000; 133: 795-799
73
Vestergaard P, Krogh K, Rejnmark L, Laurberg S, Mosekilde L.
Fracture risk is increased in Crohn's disease, but not in
ulcerative colitis. Gut 2000; 46: 176-181
74
van Staa TP, Cooper C, Brusse LS, Leufkens H, Javaid MK, Arden NK.
Inflammatory bowel disease and the risk of
fracture. Gastroenterology 2003; 125: 1591-1597
75
Stockbrugger RW, Schoon EJ, Bollani S, Mills PR, Israeli E,
Landgraf L, Felsenberg D, Ljunghall S, Nygard G, Persson T,
Graffner H, Bianchi Porro G, Ferguson A. Discordance between the degree of
osteopenia and the prevalence of
spontaneous vertebral fractures in Crohn's disease. Aliment Pharmacol
Ther 2002; 16: 1519-1527.
76
Bernstein CN, Blanchard JF, Metge C, Yogendran M. The association
between corticosteroid use and development of
fractures among IBD patients in a population-based database. Am J
Gastroenterol 2003; 98: 1797-1801
77
Viereck V, Emons G, Lauck V, Frosch KH, Blaschke S, Grundker C,
Hofbauer LC. Bisphosphonates pamidronate and
zoledronic acid stimulate osteoprotegerin production by primary human
osteoblasts. Biochem Biophys Res Commun 2002;
291: 680-686
78
Vidal NO, Brandstrom H, Jonsson KB, Ohlsson C. Osteoprotegerin mRNA
is expressed in primary human osteoblast-like
cells: down-regulation by glucocorticoids. J Endocrinol 1998;
159: 191-195
79
Redlich K, Hayer S, Maier A, Dunstan CR, Tohidast-Akrad M, Lang S,
Turk B, Pietschmann P, Woloszczuk W,
Haralambous S, Kollias G, Steiner G, Smolen JS, Schett G. Tumor necrosis
factor alpha-mediated joint destruction is
inhibited by targeting
osteoclasts with osteoprotegerin. Arthritis Rheum 2002; 46:
785-792
80
Bernstein CN, Bector S, Leslie WD. Lack of relationship of calcium
and vitamin D intake to bone mineral density in
premenopausal women with inflammatory bowel disease. Am J
Gastroenterol 2003; 98: 2468-2473
81
Schulte CM, Dignass AU, Goebell H, Roher HD, Schulte KM. Genetic
factors determine extent of bone loss in inflammatory
bowel disease. Gastroenterology 2000; 119: 909-920
82
Haderslev KV, Tjellesen L, Sorensen HA, Staun M. Alendronate
increases lumbar spine bone mineral density in patients
with Crohn's disease. Gastroenterology 2000; 119:
639-646
83
Reffitt DM, Meenan J, Sanderson JD, Jugdaohsingh R, Powell JJ,
Thompson RP. Bone density improves with disease
remission in patients with inflammatory bowel disease. Eur J
Gastroenterol Hepatol 2003; 15: 1267-1273
84
American Gastroenterological Association medical position statement:
guidelines on osteoporosis in gastrointestinal
diseases. Gastroenterology 2003; 124: 791-794
85
Schulte CM. Review article: bone disease in inflammatory bowel
disease. Aliment Pharmacol Ther 2004; 20 Suppl 4:
43-49
86
Buxton EC, Yao W, Lane NE. Changes in serum receptor activator of
nuclear factor-kappaB ligand, osteoprotegerin, and
interleukin-6 levels in patients with glucocorticoid-induced osteoporosis
treated with human parathyroid hormone (1-34). J
Clin Endocrinol Metab 2004; 89: 3332-3336
87
Miehsler W, Reinisch W, Valic E, Osterode W, Tillinger W,
Feichtenschlager T, Grisar J, Machold K, Scholz S, Vogelsang
H, Novacek G. Is inflammatory
bowel disease an independent and disease specific risk factor for
thromboembolism? Gut
2004;
53: 542-548
88
Grip O, Svensson PJ, Lindgren S. Inflammatory bowel disease
promotes venous thrombosis earlier in life. Scand J
Gastroenterol
2000; 35: 619-623
89
Talbot RW, Heppell J, Dozois RR, Beart RW Jr. Vascular
complications of inflammatory bowel disease. Mayo Clin Proc
1986; 61:
140-145
90
Solem CA, Loftus EV, Tremaine WJ, Sandborn WJ. Venous
thromboembolism in inflammatory bowel disease. Am J
Gastroenterol 2004; 99:
97-101
91
Papa A, De Stefano V, Danese S, Gasbarrini A, Gasbarrini G.
Thrombotic complications in inflammatory bowel disease: a
multifactorial etiology. Am J
Gastroenterol 2001; 96: 1301-1302
92
Cattaneo M, Vecchi M, Zighetti ML, Saibeni S, Martinelli I, Omodei
P, Mannucci PM, de Franchis R. High prevalence of
hyperchomocysteinemia in patients with
inflammatory bowel disease: a pathogenic link with thromboembolic
complications? Thromb Haemost
1998; 80: 542-545
93
Oldenburg B, Fijnheer R, van der Griend R, vanBerge-Henegouwen GP,
Koningsberger JC. Homocysteine in inflammatory
bowel disease: a risk factor for
thromboembolic complications? Am J Gastroenterol 2000; 95:
2825-2830
94
Papa A, Danese S, Grillo A, Gasbarrini G, Gasbarrini A. Review
article: inherited thrombophilia in inflammatory bowel
disease. Am J Gastroenterol
2003; 98: 1247-1251
95
Oldenburg B, Van Tuyl BA, van der Griend R, Fijnheer R, van Berge
Henegouwen GP. Risk factors for thromboembolic
complications in inflammatory bowel
disease: the role of hyperhomocysteinaemia. Dig Dis Sci 2005;
50: 235-240
96
Oldenburg B, Koningsberger JC, Van Berge Henegouwen GP, Van Asbeck
BS, Marx JJ. Iron and inflammatory bowel
disease. Aliment Pharmacol Ther
2001; 15: 429-438
97
Crawford J. Anemia and lung cancer. Lung Cancer 2002;
38: S75-S78
98
Wang CQ, Udupa KB, Lipschitz DA. Interferon-gamma exerts its negative regulatory effect
primarily on the earliest stages
of murine erythroid progenitor cell
development. J Cell Physiol 1995; 162:
134-138
99
Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory
cytokines on hypoxia-induced erythropoietin production.
Blood 1992; 79:
1987-1994
100
Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD.
Anemia of chronic disease in rheumatoid arthritis is
associated with increased apoptosis of
bone marrow erythroid cells: improvement following anti-tumor necrosis
factor-
alpha antibody therapy. Blood
2002; 100: 474-482
101
Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and
inflammatory bowel diseases. Gut 2004; 53:
1190-1197
102
Gasche C, Waldhoer T, Feichtenschlager T, Male C, Mayer A,
Mittermaier C, Petritsch W. Prediction of response to iron
sucrose in inflammatory bowel
disease-associated anemia. Am J Gastroenterol 2001; 96:
2382-2387
103
Gasche C. Complications of inflammatory bowel disease.
Hepatogastroenterology
2000; 47: 49-56
104 Caudarella R, Rizzoli E,
Pironi L, Malavolta N, Martelli G, Poggioli G, Gozzetti G, Miglioli M.
Renal stone formation in
patients with inflammatory bowel disease.
Scanning Microsc 1993; 7: 371-379
105 Kreisel W, Wolf LM, Grotz W, Grieshaber M. Renal
tubular damage: an extraintestinal manifestation of chronic
inflammatory bowel disease. Eur J Gastroenterol Hepatol
1996; 8: 461-468
106
Solem
CA, Loftus EV Jr, Tremaine WJ,
Pemberton JH, Wolff BG, Sandborn WJ. Fistulas to the urinary system in Crohn's
disease: clinical features and
outcomes. Am J Gastroenterol 2002; 97: 2300-2305
107
Fernandez-Castroagudin J, Brage Varela A, Lens Neo XM,
Martinez Castro J, Abdulkader I. Renal amyloidosis as initial
clinical manifestation of Crohn's
disease. Gastroenterol Hepatol 2002; 25:
395-397
108
Shaer AJ, Stewart LR, Cheek DE, Hurray D, Self SE. IgA
antiglomerular basement membrane nephritis associated with
Crohn's disease: a case report and
review of glomerulonephritis in inflammatory bowel disease.
Am J Kidney Dis 2003;
41: 1097-1109
109
Jensen
EJ, Baggenstoss AH, Bargen JA.
Renal lesions associated with chronic
ulcerative colitis. Am J Med Sci 1950;
219: 281-290
110
Druschky A, Heckmann J, Engelhardt A, Neundorfer. Myositis--a rare
complication of Crohn disease. Fortschr Neurol
Psychiatr 1996; 64:
422-424
111
Moormann B, Herath H, Mann O, Ferbert A. Involvement of the
peripheral nervous system in Crohn disease. Nervenarzt
1999; 70: 1107-1111
112
Kraus JA, Nahser HC, Berlit P. Lymphocytic encephalomyeloneuritis
as a neurologic complication of ulcerative colitis. J
Neurol Sci 1996; 141:
117-119
113
Nash CL, Panaccione R, Sutherland LR, Meddings JB. Giant cell
myocarditis, in a patient with Crohn's disease, treated
with etanercept--a tumour necrosis
factor-alpha antagonist. Can J Gastroenterol 2001; 15:
607-611
114
Orii S, Chiba T, Nakadate I, Fujiwara T, Ito N, Ishii M, Oana S,
Chida T, Kudara N, Terui T, Yamaguchi T, Suzuki K.
Pleuropericarditis and disseminated
intravascular coagulation in ulcerative colitis. J Clin
Gastroenterol 2001; 32 :251-254
115
Stein RB, Hanauer SB. Comparative tolerability of treatments
for inflammatory bowel disease. Drug Saf 2000; 23:
429-
448
116
Baker DE, Kane S. The short- and long-term safety of
5-aminosalicylate products in the treatment of ulcerative colitis.
Rev Gastroenterol Disord 2004;
4: 86-91
117
Lemann M, Zenjari T, Bouhnik Y, Cosnes J, Mesnard B, Rambaud
JC, Modigliani R, Cortot A, Colombel JF. Methotrexate
in Crohn's disease: long-term efficacy
and toxicity. Am J Gastroenterol 2000; 95:
1730-1734
118 Sandborn
WJ, Hanauer SB. Infliximab in the treatment of Crohn's disease: a
user's guide for clinicians. Am J
Gastroenterol 2002; 97:
2962-2972
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