Extraintestinal manifestations and complications in inflammatory bowel diseases

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) that often involve organs other than those of the gastrointestinal tract. These nonintestinal affections are termed extraintestinal symptoms. Differentiating the true extraintestinal manifestations of inflammatory bowel diseases from secondary extraintestinal complications, caused by malnutrition, chronic inflammation or side effects of therapy, may be difficult. This review concentrates on frequency, clinical presentation and therapeutic implications of extraintestinal symptoms in inflammatory bowel diseases. If possible, extraintestinal manifestations are differentiated from extraintestinal complications. Special attention is given to the more recently described sites of involvement; i.e. thromboembolic events, osteoporosis, pulmonary involvement and affection of the central nervous system.

Key Words: Inflammatory bowel diseases; Crohn’s disease; Ulcerative colitis; Extraintestinal manifestations; Complications; Therapy

INTRODUCTION

Crohn’s disease (CD) and ulcerative colitis (UC) are the main entities of chronic inflammatory bowel diseases (IBD). Although in most cases the gastrointestinal tract is mainly affected, both ulcerative colitis and Crohn’s disease are systemic disorders that often involve other organs. These nonintestinal affections are termed extraintestinal symptoms and may not always coincide with the underlying bowel disease. Extraintestinal disease can involve almost every organ system. The organs most commonly involved include the skin, eyes, joints, biliary tract and lungs. Some symptoms, such as oral lesions, gallstones, pancreatitis, nephrolithiasis and amyloidosis, are more associated with CD than with UC. Other symptoms, e.g. skin and eye manifestations, are equally seen in both CD and UC.

Several factors may be responsible for extraintestinal organ involvement in IBD and sometimes it can be difficult to differentiate the true extraintestinal manifestations (EIMs); i.e. primary systemic affection by the disease itself, from secondary extraintestinal complications of the disease, caused for example by malnutrition, chronic inflammation or side effects of therapy. Some of these EIMs may not correlate with disease activity (primary sclerosing cholangitis and ankylosing spondylitis) but in general EIMs tend to follow the clinical course of IBD and may have a high impact on quality of life, morbidity and even mortality in these patients.

The reported frequency of EIMs in patients with IBD varies from 6%-47%[1-4]. The development of one EIM appears to increase the susceptibility of developing other EIMs. An overlap of EIMs is particularly observed with peripheral arthritis, erythema nodosum, affection of the biliary tract and the eyes, in concordance with the hypothesis of a common pathogenic pathway. Some authors discuss an autoimmune reaction towards an isoform of tropomyosin (Tropomyosin related peptide), which is expressed in eye (non-pigmented ciliary epithelium), skin (keratinocytes), joints (chondrocytes), biliary epithelium and the gut[5,6].

The high concordance in EIMs in siblings and first degree relatives with IBD[7] suggests a common genetic background. Crohn’s disease and ulcerative colitis are polygenic disorders and certain susceptibility genes in the major histocompatibility complex (MHC) region on chromosome 6 seem to be linked to EIMs in IBD. In CD, extraintestinal co-morbidities are more commonly observed in patients with HLA-A2, -DR1 and DQw5, whereas in ulcerative colitis, the genotypes HLA-DRB1*0103, B*27 and B*58 are linked with EIMs involving the joints, skin and eyes[8-10]. Fifty to eighty percent of IBD patients with ankylosing spondylitis are HLA*B27 positive[11]. Furthermore, in UC the haplotype HLA B8/DR3 is associated with primary sclerosing cholangitis (PSC) and may also be linked to other autoimmune diseases (e.g. celiac disease, autoimmune hepatitis, myasthenia gravis)[12]. Interestingly, the NOD2 gene in CD seems to be associated not only with ileal disease in CD but also with sacroileitis[13].

In the following, an overview of the involvement of the different organ systems in IBD will concentrate on frequency, clinical presentation and therapeutic implications. In some cases, a differentiation of extraintestinal manifestations and extraintestinal complications will be given. Besides the classical extraintestinal manifestations, such as skin, joints, eyes and the hepatobiliary system, special attention will be given to the rarer, more recently described involvements, such as thromboembolic events, osteopenia and osteoporosis, pulmonary involvement and affection of the central nervous system.

MUSCULOSCELETAL MANIFESTATIONS

Joint manifestations are the most common EIMs in IBD and occur in approximately 20%-30% of patients[3,14]. Males and females are equally affected. Symptoms may range from arthralgia only to acute arthritis with painful swollen joints. Both peripheral arthritis and axial arthritis can occur.

Peripheral arthritis

Peripheral arthritis in IBD is quite distinct from specific forms of arthritis since there is little or no joint destruction, and tests for rheumatoid factor, antinuclear antibody and LE factor are negative. The prevalence of all forms of peripheral arthritis is reported to be between 5%-10% in UC and 10%-20% in CD, respectively[6,15], not considering asymptomatic patients under medical treatment. There are two types of peripheral arthritis in IBD[15] that should be distinguished from unspecific myalgia or arthralgia:

Type 1 (pauciarticular) arthritis affects less than five large joints (predominantly of the lower limbs) and the swelling is acute and often self-limiting. Type I arthritis is related to disease activity of the underlying bowel disease. The mean duration is 5 weeks; some 25%-40% of patients will have recurring arthritis. Type 2 (polyarticular) arthritis is a symmetrical polyarthritis, frequently involving five or more of the small joints (e.g. knuckle joints). Its course is independent of disease activity and may last for several months.

The etiology of peripheral arthritis in IBD is thought to be a combination of genetic predisposition and exposition to luminal (bacterial) bowel contents. Type 1 IBD arthritis is associated with HLA-DRB1*0103, HLA-B*27 and HLA-B*35, whereas type 2 IBD arthritis is associated with HLA-B*44 and MHC class I chain-like gene A, which is a non classical HLA gene located near the HLA-B on chromosome 6[8,10,16]. The site of intestinal inflammation is of particular interest concerning the pathogenesis of joint inflammation since CD patients with colonic involvement are at higher risk of developing arthritis than those with isolated small bowel disease. Furthermore the incidence of new joint complications significantly decreases after ileocecal resection (even when corrected for the time spent in remission after surgery), suggesting that bacterial overgrowth proximal to the ileocecal valve plays an important role in the pathogenesis of extraintestinal joint inflammation[6].

The diagnosis of peripheral arthritis in IBD is made clinically since radiographic findings do not show erosions or deformities. In persisting disease, a positive rheumatic factor should be excluded. In acute swelling, septic arthritis, fistulating arthritis or gout may be excluded by joint aspiration.

Treatment: Type 1 arthritis is related to disease activity and therefore therapy of the underlying IBD is the treatment of choice. Especially in patients with relapsing arthritis (HLA-DRB*0103), 5-ASA treatment should be switched to sulfasalazine, thereby taking advantage of the antiarthritic effect of sulfapyridine to minimize the risk of relapse. In addition, symptomatic treatment is often sufficient. For analgetic therapy, NSAID’s and COX-2 selective inhibitors should be avoided, if possible, due to their potential to activate the underlying IBD[17]. In severe cases, symptoms relief can be achieved by intra-articular steroid injection. Type 2 IBD arthritis generally requires long-term treatment. In persisting disease, sulfasalazine should be initiated at an initial dose of 2 × 500 mg per day, increasing the daily dose by 1000 mg every two weeks towards the maximum dose of 3 × 1500 mg or until symptoms improve. If not effective despite 12 wk of continuing treatment, immunosuppression with methotrexate (7.5 mg po once weekly) should be started. The dose can be increased by 2.5 mg steps in monthly intervals up to the maximum dose of 25 mg per week. Concomitant folic acid (5 mg po 24 h following methotrexate) is recommended to reduce side effects. Systemic corticosteroids may be necessary to control symptoms.

Axial arthropathies

The axial arthropathies are not associated with disease activity of IBD. Spondylitis occurs in 1%-26% of patients with IBD and males are more often affected than females. Both progressive ankylosing spondylitis and sacroiliitis (sometimes asymptomatic) may occur. Plain radiographs of the sacroiliac joints show uni- or bilateral sclerosis and/or erosions. The diagnostic gold standard is magnetic resonance imaging (MRI) with a high sensitivity in detecting sacroiliitis even in the absence of symptoms.

Ankylosing spondylitis

Ankylosing spondylitis (AS) affects the vertebral column by progressive ankylosis of the vertebral facet joints and the sacroiliac joint (Figure 1). The prevalence of AS in IBD (1%-6%) is higher than in the general population (0.25%-1%)[18]. In contrast, the association with HLA*B27 is considerably weaker than in idiopathic AS with only 50%-80% of IBD patients being positive for HLA B*27 compared to 94% in the general population[11]. Again, bacteria and gut inflammation seem to play an important role in the pathogenesis of AS. Interestingly, ileocolonoscopy in patients with idiopathic spondylarthropathies reveals ileal inflammation in more than two thirds of patients[19].

Figure 1 X-ray thoracic spine demonstrating ankylosing spondylitis (Bechterew's disease) with syndesmophytes/bamboo spine in a patient with CD.

The clinical course of AS in IBD is similar to idiopathic AS, and disease progression leads to increasing immobility of the spine resulting in ankylosis (bamboo spine). Secondary to reduced chest expansion, poor lung expansion with fibrosis and dilatation of the aortic root can occur. AS is associated with peripheral arthritis in about 30% of patients and with uveitis in 25% of patients.

Treatment: There is no causative treatment and therefore physical therapy is of particular importance to maintain mobility of the spine. In the absence of active IBD, NSAID are the drugs of choice, otherwise acetaminophen or tramadol are preferred. Steroid injection (MRI-guided) into the sacroiliac joint may be an option in patients with severe low back pain[20]. Sulfasalazine may be used, but is more effective in associated peripheral arthritis. The first line immunosuppressant in patients with AS and IBD is methotrexate. Anti-TNF-strategies should be reserved for severe cases. Experience is limited to small case series, but improvement of both spondylarthropathy and active bowel disease has been reported in CD with infliximab[21-23]. Etanercept is effective in spondylarthropathies[24,25] but the efficacy in CD has not yet been demonstrated.

Isolated sacroiliitis

It may occur in patients with IBD but most patients are asymptomatic and the disease is non-progressive. Prevalence depends on the radiological method used and varies from 18% in plain radiographs and 32% in CT imaging to 52% in radioisotope scintigraphy. Isolated sacroiliitis seems not to be associated with HLA*B27[6]. Asymptomatic HLA*B27 negative patients with normal spinal mobility do not require specific treatment.

Osteoporosis

Patients with IBD have an increased risk of developing osteoporosis, associated with fragility fractures and morbidity. The overall prevalence of osteoporosis in IBD is approximately 15% but is more prevalent with older age; the overall relative risk of fractures is 40% greater when compared to the general population[26,27]. Vertebral fractures often occur spontaneously or after minimal trauma and it is estimated that only one-third of vertebral fractures come to clinical attention[28]. X-ray images of the spine most commonly show wedge or compression deformities. A variety of studies have demonstrated both decreased bone mineral density (BMD) in patients with IBD[29-38], and increased rates of bone loss when followed longitudinally[34,39,40] in comparison to healthy controls. The current Gold standard for measuring bone mass is dual-energy X-ray absorptiometry (DEXA)[41].

The pathogenesis of osteoporosis in IBD is multifactorial. Important pathogenetic factors in IBD include the cumulative steroid dose, hypogonadism induced by IBD (absence of menstrual period in women), malabsorption of calcium and vitamin D, low body mass index and disease activity/elevated inflammatory cytokines[42]. Other risk factors are previous fragility fracture, a positive family history, concomitant liver/endocrine disease (hyperthyroidism, hyperparathyroidism), immobilization and life style risk factors (smoking, excessive alcohol intake, physical inactivity). The multifactorial pathogenesis of bone loss in IBD makes it difficult to assess the importance of each single contributing factor. The results of a study from Norway indicate that disease activity and corticosteroid therapy are the most important factors involved in bone loss in CD patients[43]. However, it remains unclear whether the bone loss is related to the disease or to its treatment.

Biochemical markers of bone turnover (e.g., osteocalcin, bone specific alkaline phosphatase, carboxyterminal propeptide procollagen type 1, urinary deoxypyridinoline, pyridinoline, carboxytelopeptide of type I collagen, N-telopeptide cross-linked type I collagen) do not correlate sufficiently with current BMD for routine use[30,33,35,44-46] and should be confined to research studies[26].

Treatment: Few IBD patients are receiving optimal bone-sparing therapy, highlighting the importance of increasing awareness of osteoprosis in managing these patients[38]. Preventing bone loss should begin with an attempt to limit corticosteroid-induced bone loss. This can be done by minimizing the corticosteroid dosage, substituting with budesonide when appropriate[47,48], administering other steroid-sparing immunomodulators once corticosteroid dependence becomes evident, or by prescribing additional agents that enhance bone health. The administration of calcium and vitamin D[49] appears to maintain or enhance bone mass[26]. Bisphosphonates are of unclear additional benefit to the majority of patients who are at low fracture risk. In a small trial in Denmark, one year of daily alendronate treatment p.o. improved BMD in the spine[50]. Bisphosphonates (etidronate, risedronate, alendronate) are effective in preventing bone loss in steroid treated patients, but only few patients with IBD have been included in these trials[51-54]. Nasal or s.c. calcitonin can be considered as an alternative treatment approach when bisphosphonates are contraindicated or poorly tolerated. Testosterone replacement should be considered in hypogonadal men[26], estrogen replacement in postmenopausal women[55].

Osteomalacia

Osteomalacia is a rare complication of IBD, most likely occurring in patients with severe CD and multiple intestinal resections[56], resulting from prolonged and severe vitamin D deficiency. Though both osteoporosis and osteomalacia result in low BMD, apart from elevated bone alkaline phosphatase levels, osteomalacia can only be distinguished from osteoporosis by bone biopsy.

Joint complications in IBD

Complications involving the joints should always be considered and have to be distinguished from sterile joint inflammation, since steroid treatment can cause osteonecrosis (avascular necrosis of the bone). Patients on immunosuppressive therapy are at increased risk of septic arthritis. In CD, fistulization may cause bacterial infection of the iliosacral joint. Rarely a psoas abscess can cause septic hip arthritis.

MUCOCUTANEOUS MANIFESTATIONS

Erythema nodosum, pyoderma gangraenosum and oral ulceration are the most common cutaneous manifestations in IBD and are usually related to disease activity but sometimes may take an independent course. All patients presenting with IBD should be examined for cutaneous manifestations.

Erythema nodosum

It is the most common skin manifestation in IBD affecting up to 15% of CD patients, with a female predominance[1,6,14]. Erythema nodosum (EN) affects the subcutaneous fat (septal panniculitis), causing tender erythematous nodules usually located on the shins (Figure 2). EN normally heals without ulceration and the prognosis is good. The clinical picture is typical and biopsy rarely is required for diagnosis. The etiology of EN is unknown, however there is a genetic association with a distinct HLA region on chromosome 6 (HLA-B^)[9]. EN characteristically parallels intestinal disease activity. There is an association with other EIMs such as arthritis and uveitis[14,15]. Treatment of the underlying bowel disease usually results in improving EN lesions and at least 25% of EN will heal spontaneously. There is no specific treatment for EN, but symptomatic therapy should comprise pain medication and oral steroids may be given in severe cases. Immunosuppressive treatment is not necessary. In the absence of active bowel disease, other causes of EN, such as sarcoidosis or post-streptococcal infection, should be taken into consideration.

Figure 2 Erythema nodosum in a patient with CD.

Pyoderma gangrenosum (PG)

Pyoderma gangrenosum occurs in 0.5%-2% of both patients with UC and CD and may take a course independent of disease activity (Figure 3). Conversely, 36%-50% of patients with PG suffer from IBD. PG appears as a tender erythematous papule evolving into a livid pustule with central necrosis and subsequent ulceration, occurring in single or multiple lesions. The ulcer often has a irregular outline and is sharply demarcated with a heaped-up mushy violaceous border, surrounded by a erythematous zone (Figure 1). Often minor trauma, needle stitches or biopsy can induce new PG lesions (pathergy phenomenon). PG lesions have a predilection for the lower limbs but may occur in any area of the skin, sometimes even as peristomal ulcers[57]. The diagnosis of PG is made clinically; nevertheless skin biopsy of the border of the ulcer may be performed to rule out vasculitis or infection. There are no pathognomonic histologic features, generally revealing only diffuse neutrophilic infiltration and dermolysis.

Figure 3 Pyoderma gangrenosum in a patient with CD.

PG is the most severe skin manifestation in IBD. PG is painful and often persisting despite adequate therapy. Without treatment, PG can last for years and ulcers may spread. Therefore, aggressive and early treatment is required. Local wound care consists of dressings, mild débridement of necrotic material and eschar (continuous wet saline compressions, topical enzymatic ointment, hydrocolloid dressings similar to common ulcer treatment). Topical tacrolimus has also emerged as potentially useful therapy[58]. First line systemic treatment in PG is high dose prednisolone. Intravenous pulse therapy over three days is highly effective. Careful tapering should be started with clinical improvement. In steroid dependent or steroid refractory (no improvement within 5 d) cases, immunosuppressive therapy should be initiated. In mild cases a combination of steroids with dapsone has been successfully used with an initial dosage of dapsone 100 mg po/d, gradually increasing to 200-300 mg/d[59]. In more severe cases cyclosporine or tacrolimus are effective. Steroid dependent patients require immunosuppressive treatment with azathioprine/6-mercaptopurine. A variety of other treatments (thalidomide, topical cromoglycate, clofazimine, plasmapheresis, granulocyte apheresis, hyperbaric oxygen) have been reported anecdotally. Surgical intervention should be avoided, if possible, since it may induce pathergy. In resistant cases infliximab at a dose of 5 mg/kg has been used successfully[59,60]. PG often takes a prolonged course, but in general will be controllable with medical therapy. About 35% of patients will experience relapsing PG.

Oral ulcerations

Oral aphthous ulcers occur in at least 10% of patients with UC and 20%-30% with CD and rapidly resolve once remission is achieved. Stomatitis, as an adverse event of methotrexate therapy, should be taken into account.

Miscellaneous skin lesions

Many other skin affections have been described in patients with IBD, such as Sweet’s syndrome (neutrophilic dermatosis)[61] (Figure 4), leukocytoclastic vasculitis, psoriasis, epidermolysis bullosa acquisita, and cutaneous polyarteriitis nodosa. Since these diseases have been mainly reported as single case reports, they probably occur coincidentially rather than as a true EIM. Angular cheilitis in nearly 8% of patients with CD often is a sign of iron deficiency.

Figure 4 Sweet syndrome: papulosquamous exanthema in a patient with UC.

EYE MANIFESTATIONS

Two to five percent of patients with IBD experience ocular manifestations[62]. The manifestations range from conjunctivitis to more significant inflammation, including iritis, episcleritis, scleritis and anterior uveitis. Mild cases of conjunctivitis may be diagnosed clinically, but in other cases early referral to an ophthalmologist is important for accurate diagnosis.

Episcleritis

Episcleritis is less common in UC than in CD, presents as an infection of the ciliary vessels and an inflammation of the episcleral tissues and does not affect visual acuity. Inflammation episodes tend to occur in association with active bowel disease. Successful treatment consists of both topical corticosteroids and treatment of the underlying bowel disease. Scleritis affects deeper layers of the eye and can cause lasting damage if untreated.

Uveitis

Uveitis is less common than episcleritis and occurs in 0.5%-3% of patients. It does not affect visual acuity unless it involves the posterior segment. Uveitis frequently presents bilaterally, is insidious in onset and chronic in duration. It is more common in females and may not parallel bowel disease activity. On slit-lamp examination uveitis presents as a perilimbic edema and “inflammatory flare” in the anterior chamber. Conjunctival vessel injection and corneal clouding may also be seen. An acute episode of uveitis can lead to permanent damage of the eye with iris atrophy, lens deposits or synechiae. More aggressive therapy may be necessary, especially when the posterior chamber is affected. Prompt diagnosis and therapy with topical and systemic steroids is crucial and sometimes intraocular injections of corticosteroids may be necessary. Steroid treatment should be continued for four weeks before tapering if uveitis is under control. Iridospasm is relieved by topical mydriatic eyedrops. Successful treatment for IBD-associated uveitis with infliximab was first described in one CD patient having a suitable extraintestinal constellation (uveitis and sacroileitis)[63]. In rheumatoid arthritis with severe refractory uveitis, infliximab was effective but with an unexpected high rate of side effects[64].

Ocular complications in IBD include keratopathy and night blindness resulting from malabsorption of vitamin A. Cataract development is a severe side effect of steroid therapy, therefore regular ophthalmologic examination should be considered. Rare eye manifestations are retinal vascular disease (central vein occlusion or vasculitis), peripheral corneal ulcers, corneal infiltrates and central serous chorioretinopathy with bullous retinal detachment.

HEPATOBILIARY MANIFESTATIONS

Primary sclerosing cholangitis

In UC, the main hepatic EIM is primary sclerosing cholangitis (PSC), a chronic inflammatory disease of the biliary tree, occurring in approximately 3% of all patients (Figure 5). The diagnosis is made by endoscopic or magnetic resonance cholangiography, showing beading, irregularity, and stricturing of intrahepatic and extrahepatic ducts. Histology ranges from obliterating concentric fibrosis of the bile ducts to chronic inflammatory infiltrates in the portal tracts resulting in interface hepatitis. Low titres of autoantibodies against smooth muscle, parietal cells, and nuclear antigens are common, and high titres of autoantibodies to neutrophils (p-ANCAs)[65], showing a perinuclear pattern of staining, have been described. The majority (70%) of patients have the HLA-DR3, B8 haplotype.

Figure 5 ERC demonstrating primary sclerosing cholangitis in a patient with CD.

Treatment

Ursodeoxycholic acid has been suggested to delay disease progression[66]. Although not avoiding the progression of liver disease, ursodeoxycholic acid has been demonstrated to exhibit chemopreventive effects and reduce the risk of colorectal dysplasia in ulcerative colitis[67,68]. This is of importance since patients with UC and concomitant PSC have a significantly higher risk of developing colorectal neoplasia compared with patients having UC only[69]. PSC is seen as a premalignant condition for the development of cholangiocarcinoma as well.

Early symptomatic treatment of cholestasis is mandatory to avoid septic complication and consists of endoscopic dilatation with or without stent insertion. PSC is slowly progressive and independent of the course of UC, developing the complications of portal hypertension and chronic liver failure. For end-stage liver disease, liver transplantation remains an option.

PSC may occur in 4% of patients with CD as well, usually in those with colonic disease. Inflammatory changes of the small ducts show a normal cholangiogram and pericholangitis on liver biopsy[70].

Hepatobiliary complications

Gallstones are frequent in patients with CD, of which 25% develop gallstones mainly due to malabsorption of bile salts from the inflamed terminal ileum. Abnormalities of liver function (elevated serum aminotransferase and alkaline phosphatase) are common in patients with malnutrition, sepsis, and fatty liver due to severe attacks of IBD. These correlate with disease activity and return to normal once remission is achieved. Factors favouring fatty infiltration of the liver in severely ill patients are poor nutrition and often concomitant steroid therapy.

PANCREATIC MANIFESTATIONS

There is an increased risk for acute as well as chronic pancreatitis in IBD[71-73] documented by a multitude of case reports and case series.

Acute pancreatitis

Especially in cases of acute pancreatitis, it may be difficult to determine the true incidence of EIM[74]. Many drugs in IBD treatment have the potential to induce acute pancreatitis (e.g. salicylates, azathioprine and 6-mercaptopurine, rarely corticosteroids). Drug-induced pancreatitis typically occurs within the first weeks after commencing drug-therapy[75], the course is usually mild and resolves quickly after discontinuing the drug. Especially in CD regional inflammatory complications due to duodenal/papillary involvement or biliary complications should be considered. Nevertheless, after excluding extraintestinal complications, an increased risk for idiopathic pancreatitis remains in patients with IBD (1%-1.5%) that should be considered as true extraintestinal involvement.

Pancreatic autoantibodies have been found in up to 40% of CD patients[76]. In contrast to earlier reports[77] the prevalence seems to be increased in both CD and UC patients as well as in first-degree relatives[78]. The relevance for disease is still unclear, however. In a series with 64 antibody-positive CD patients the proportion suffering from exocrine insufficiency was 27% compared to 8% in antibody negative patients[79]. Further studies are needed to show whether these antibodies, apart from their diagnostic relevance for IBD, actually play a role in pathogenesis and whether they can help to identify patients at risk of developing an EIM involving the pancreas.

Chronic pancreatitis

Endoscopic retrograde pancreatography (ERP) is still the most sensitive and specific test for chronic pancreatitis. There are several reports on intrapancreatic duct changes in patients with IBD[80,81]. Pancreatic function has been investigated as well. In the study of Heikius, the exocrine function was found to be decreased in only 4% of patients using the secretin test. These results are consistent with two other studies that diagnosed exocrine insufficiency in a minority of IBD patients only[73,82]. In all studies, chronic alcohol ingestion as a potential cause for chronic pancreatitis had been excluded. The pathogenesis of chronic pancreatitis in patients with IBD remains unclear. Since there has only been one documented case of pancreatic granuloma in Crohn’s disease[83], pancreatitis has been considered to be caused by circulating inflammatory mediators rather than directly-involved pancreatic tissue. As discussed above, autoantibodies against pancreatic tissue may play a role in the development of exocrine insufficiency.

THROMBOEMBOLIC EVENTS

Patients with IBD are at increased risk of developing thromboembolic complications. The incidence of deep vein thrombosis and pulmonary embolism is increased and is a major cause of mortality in IBD. Venous thrombembolism is more common than arterial embolism. Conventional risk factors, such as prolonged immobilization, hospitalization, sepsis, surgery or invasive procedures, contribute to this increased risk especially in active or complicated IBD. In severe disease, thrombocytosis and increased concentrations of many clotting factors that behave as acute phase proteins, lead to a procoagulatory status. The majority of IBD patients with thromboembolic events have active disease[84]. However, a recent study demonstrated nicely that IBD, as such, is a risk factor for thromboembolic events. Comparing patients with IBD, rheumatoid arthritis and celiac disease to age and sex-matched controls, they found that patients with IBD have a 3.6-fold increased risk of experiencing thromboembolic events in contrast to the other chronic inflammatory diseases that have no increased risk[85].

There is no consistent evidence that inherited thrombophilia is associated with IBD. The main established genetic risk factors have not been found to be increased in IBD[86-88]. In more than half of patients with thrombosis, no predisposing factor is evident[86]. Therefore, screening for these risk factors seems to be justified only in the case of a personal or a family history of thromboembolism. Hyperhomocysteinemia, more common in IBD patients than in controls, is associated with an increased risk of thrombembolism as well. To date it is controversial if polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene leading to hyperhomocysteinemia are more frequent in IBD patients compared to healthy controls[87,89,90]. Lack of Vitamin B6, B12 or folate or the use of folate-inhibiting drugs (methotrexate, sulfasalzine) can contribute to acquired hyperhomocysteinemia.

Corticosteroid treatment may cause a hypercoagulable state with increased risk of thrombosis, but systemic data pointing towards a significant association is missing. In general, all hospitalized patients with IBD should receive low-dose heparin for thromboprophylaxis unless there is severe bleeding.

MANIFESTATIONS OF THE KIDNEYS AND THE URINARY TRACT

Glomerulonephritis

There are several reports on glomerulonephritis in patients with IBD. Many kinds of histology and clinical course, ranging from minimal change nephropathy to rapidly progressive glomerulonephritis, have been described[91-94]. A true extraintestinal manifestation is difficult to prove, however, and the combination of glomerulonephritis and IBD may well be coincidental.

Interstitial nephritis and tubular proteinuria

Again, it is difficult to make a distinction between EIM and side effects of medication. Single cases of interstitial nephritis have been reported in IBD. At least one case of granulomatous interstitial nephritis has been attributed to underlying CD[95], thus interstitial nephritis may represent a EIM of IBD. Medication, especially therapy with aminosalicylates, may cause interstitial nephritis as well. However, surveillance data from France[96] and the UK[97] report a low incidence of renal impairment under salicylate therapy. An additional, large epidemiologic study recently demonstrated that renal impairment is attributed to severity of the underlying IBD rather than to 5-ASA treatment[98]. This is in accordance with the fact that the frequently observed tubular proteinuria in IBD is related to disease activity and not dependent on 5-ASA treatment[99-101]. The clinical relevance of this proteinuria remains to be determined.

Renal and urinary complications

In patients with CD, uric acid and oxalate stones are common. Due to fat malabsorption luminal calcium is bound to free fatty acids. Lack of free calcium results in increased oxalate absorption, hyperoxaluria and formation of renal oxalate stones. Hyperoxaluria may cause chronic tubulointerstitial nephritis as well. Prevention treatment of oxalate stones consists of low oxalate diet and supplementation of oral calcium (1-2 g/d). The risk for uric acid stones is increased with volume depletion (e.g. due to diarrhoea, ileostomy) and a hypermetabolic state in critically ill patients. Prevention of uric acid stone recurrence consists of hydration and oral urinary alkalization.

A rare complication is renal amyloidosis (AA-Amyloidosis) due to chronic inflammation; it mainly occurs in CD and is rarer in UC. Systemic AA amyloidosis is caused by extracellular deposition of fragments of the circulating acute-phase-plasma protein (SAA). Usually the mean duration between onset of the underlying chronic disease and the occurrence of amyloidosis is at least 15 years. The diagnosis is confirmed by detection of amyloid (Congo red staining) deposits in tissue (rectum biopsy, abdominal fat aspiration). Progression of amyloidosis can be stopped by controlling inflammation. Additional genitourinary complications may be caused by (enterovesical) fistula formation, perivesical abscesses, cystitis and obstructive uropathy.

PULMONARY MANIFESTATIONS

Various pulmonary manifestations have been reported in IBD including small and large airway dysfunction as well as obstructive and interstitial lung disorders. Case reports do not show a uniform picture of disease. Various entities including bronchial hyperreagibility, bronchitis and bronchiectasis, inflammatory tracheal stenosis, interstitial pneumonitis as well as bronchiolitis obliterans organizing pneumonia (BOOP) have been described. The respiratory symptoms usually follow the onset of the IBD. Sometimes pulmonary disease, especially serositis, correlates with IBD activity. Parenchymal lung disease often develops independently of disease activity. Interestingly, colectomy seems to be a risk factor for developing pulmonary symptoms with a frequent postoperative onset[102,103].

Recently, a large population-based Canadian study reported airway disease as the most common concomitant chronic disease in patients with CD and second most common in patients with UC[3]. Patients with CD and with UC were more likely, 30%-40% and 50%-70% respectively, than controls to have asthma[3]. The high frequency of pulmonary involvement in IBD probably reflects the commonality of bronchus-associated and gut-associated lymphoid tissue[104]. Subclinical lung involvement is much more common than apparent respiratory symptoms, reported in as many as 30%-60% of patients with CD. Bronchoalveolar lavage reveals alveolitis in as much as 50% of CD patients without any clinical respiratory symptoms[105] and abnormal pulmonary function tests have been reported in 42% of IBD patients without respiratory symptoms compared to only 3% in controls[106]. Interestingly, these changes persist during remission.

Persistent airway inflammation can result in airway narrowing, dependent on the localization, resulting in tracheal stenosis, bronchiectasis or bronchiolitis obliterans. In fact, the majority of patients with IBD-related respiratory manifestations present with chronic bronchitis or bronchiectasis[102]. Chest X-rays are often unspecific; high resolution chest CT scanning may demonstrate bronchial wall thickening, dilated airways, branched opacities due to mucoid impaction[107]. In lung biopsy nonspecific inflammation, small airway fibrosis and sometimes granulomatous bronchiolitis have been reported[108,109]. The most common interstitial lung disease associated with IBD is bronchiolitis obliterans organizing pneumonia (BOOP)[102]. Chest X-ray reveals patchy focal opacities or diffuse infiltrates, while CT scanning often demonstrates pleural-based opacities and air bronchograms. Typical granulomatous interstitial lung disease in Crohn’s disease is rare and may mimic sarcoidosis with the occurrence of noncaseating granulomas and elevated CD4/CD8 ratios in bronchoalveolar lavage fluid[110-112]. Apart from airway inflammation and interstitial lung disease other pulmonary manifestations of IBD include serositis[113]. Serositis occurs as exsudative pleural effusion pericarditis, pleuropericarditis and myocarditis[107].

Complications

Pulmonary parenchymal involvement may be related to IBD, but also may be induced by drugs (e.g. mesalazine, sulfasalazine, methotrexate). Many cases of drug-induced pulmonary complications in IBD patients have been reported. Salicylates of all kinds can induce different types of interstitial lung disease, such as BOOP and granulomatous lung disease. The pulmonary toxicity of 5-aminosalicylic acid (5-ASA) is less common than with sulfasalazine, but pulmonary infiltrates, sometimes eosinophilia or BOOP may develop as well[102,114,115]. Pulmonary infiltrates with eosinophilia (PIE syndrome) can occur with or without the use of sulfasalazine or mesalamine[116]. Chest X-rays often show peripheral infiltrates typical of chronic eosinophilic pneumonia and laboratory values reveal eosinophilia. Methotrexate treatment may cause serious hypersensitivity pneumonitis or pulmonary fibrosis. Chest X-rays show diffuse alveolar or interstitial infiltrates.

Especially if patients receive combination immuno-suppression, the possibility of opportunistic pulmonary infections should be taken into account.

Treatment

It is unclear whether asymptomatic patients should receive therapy at all. However, it should be born in mind that IBD patients carry an increased mortality risk due to pulmonary disease[117-119]. Depending on the type of pulmonary complication, inhaled or systemic steroid therapy may be effective. In various forms of airway inflammation, inhalatory steroid therapy (e.g. beclomethasone up to 1200 μg/d) is generally effective, with large airway inflammation being more responsive than bronchiolitis. Patients with bronchiectasis are less likely to respond to inhaled steroids and may require oral steroids. In severe airway inflammation with upper airway obstruction, such as subglottic involvement, intravenous steroids may be required. Interstitial lung disease usually requires systemic steroids; e.g. prednisolone 0.5-1.0 mg/kg per day for a longer period of time, usually months, depending on the clinical course.

CARDIAC MANIFESTATIONS

Pericarditis or perimyokarditis with or without an effusion have been described in a few case reports on patients with active IBD. Again, it may be difficult to rule out drug toxicity since salicylates are potential culprits. However, in the Canadian population-based study, both patients with CD and UC were at an increased risk of developing pericarditis in comparison to healthy controls[3]. Age-adjusted prevalence ratios were 3.07 in CD and 3.33 in UC, respectively, although the numbers were small[120].

NEUROLOGICAL MANIFESTATIONS

The association of autoimmune neurological disorders and IBD has long been hypothesized, especially for multiple sclerosis[121-125]. Furthermore there are some sporadic reports of neuropathies in IBD such as optic neuritis[126], peripheral neuropathies[127] and (subclinical) sensorineural hearing loss[128,129]. MRI studies have shown clinical nonapparent cerebral white matter lesions in patients with IBD[130]. A recent retrospective cross-sectional study evaluated the risk of patients with IBD to develop either multiple sclerosis, optic neuritis or demyelinating disease in the pre-anti-TNF-era[131]. The authors found a small but significant association of IBD with these demyelinating diseases (OR 1.67). The risk was not found to be related to the use of steroids and/or immunosuppressive therapy with thiopurines. These results are of special interest in the light of recent reports on new unexpected adverse events of biological agents.

Recently, alarming reports on the development of progressive leucencephalopathia under treatment with natalizumab, an antibody directed against α4-integrin, have resulted in stopping all ongoing trials with this substance[132,133]. Similar observations exist on the anti-TNFα-therapeutic agents infliximab, etanercept and adalimumab[134-136] and have led to additional safety warnings concerning the use of these drugs. To date, patient numbers are too small to draw final conclusions but these agents may well accelerate the preexisting risk for demyelinating disorders in IBD patients.

Metronidazole, often used in fistulizing CD, can cause polyneuropathia if given as long term treatment. Nutritional deficiencies (Vitamin B12) should always be taken into consideration and looked for especially in long-lasting and severe disease (Table 1).

Table 1 Extraintestinal symptoms in inflammatory bowel disease.

Extraintestinal manifestations	Extraintestinal complications
Musculosceletal diseases
Peripheral Arthritis	Drug-induced osteoporosis and osteonecrosis
Ankylosing spondylitis	Bacterial infection of joints (fistulization, immunosuppression)
Isolated sacroiliitis	Septic arthritis
Metastatic Crohn’s disease
Mucocutaneous diseases
Erythema nodosum	Anal fissures
Pyoderma gangraenosum	Fistulas
Aphthous stomatitis/oral ulceration
Psoriasis?	Acrodermatitis enteropathica (Zinc deficiency)
Epidermolysis bullosa acquisita?	Purpura (Vitamin C and K deficiency)
Sweet Syndrome?	Glossitis (Vitamin B or Zinc deficiency)
Erythema exsudativum multiforme?	Hair loss (protein deficiency)
	Brittle nail (protein deficiency)
	Perlèche (Iron deficiency)
	Candidiasis (Zinc deficiency, immunosuppression)
	Mucositis/stomatitis (methotrexate)
	Drug-induced rash, allergic exanthema
	Moon-face, acne, stretch marks, skin atrophy (steroid treatment)
Ocular diseases
Anterior Uveitis	Night blindness Vitamin A deficiency
Conjunctivitis	Kerathopathy Vitamin A deficiency
Iritis	Opportunistic infections (immunosuppressants)
Skleritis/Episcleritis
Hepatobiliary diseases
Primary sclerosing cholangitis	Gall stones in Crohn’ disease
Granulomatous Crohn’s hepatitis	Fatty liver
Autoimmune chronic active hepatitis?
Biliary cirrhosis?
Pancreatic diseases
Acute pancreatitis	Drug-induced pancreatitis (5-ASA, azathioprine)
Chronic pancreatitis, exocrine insufficiency	Biliary pancreatitis in Crohn’s disease
	Duodenal involvement in Crohn’s disease
Blood and vascular diseases
Thrombembolic events	Anemia (Iron-, folate-, vitamin B12-deficiency)
Autoimmune hemolytic anemia?	Thrombocytosis, leucocytosis
Thrombocytopenic purpura (Moschcowitz Syndrome)?	Hypercoagulation: venous thrombosis, thrombembolism
Renal diseases
Tubular proteinuria	Nephrolithiasis (oxalate stones, uric acid stones)
Glomerulonephritis?	Local affection involving the urethro-genital system
	Acute interstitial nephritis (drug related SASP, 5-ASA)
Interstitial nephritis?	Drug-induced renal insufficiency (5-ASA, SASP, cyclosporine)
	Renal amyloidosis
Bronchopulmonary diseases
Chronic bronchitis/bronchiolitis/bronchiectasis	Drug-induced hypersensitivity pneumonitis
Acute laryngotracheitis/tracheal stenosis	Drug related pulmonary fibrosis (methotrexate)
Bronchiolitis obliterans organizing pneumonia	Drug-induced pleuritis
Pleuritis/serositis	Opportunistic infections (immunosuppression)
Cardiac diseases
Pericarditis	Drug-induced pericarditis (5-ASA)
Myocarditis?/perimyocarditis
Neurological diseases
Demyelinating diseases including multiple sclerosis	Peripheral neuropathy (Vitamin B12 deficiency)
Optic neuritis, sensorial hearing loss	Drug-induced leucencephalopathia (natalizumab, infliximab)
Myasthenia gravis?	Drug-induced polyneuropathia (metronidazole)

SUMMARY

In conclusion, IBD are systemic disorders and not restricted to the intestine. Recent reports on the involvement of new organ systems emphasize that almost every site of the body can be affected by the inflammatory process. The possibility of contributing disease complications, especially through the side effects of treatment, should always be born in mind. The distinction between disease and treatment side effects can be extremely difficult and may sometimes be impossible. Recent reports on multiple organ involvement, including the central nervous system, point out the importance of an increased awareness for these potential problems. In addition, these data provide additional warning concerning the use of the new biological treatment strategies. These agents have to be prescribed with care since long term experience with toxicity is limited.