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.

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 (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].

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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.

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.

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 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.

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.

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.

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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.

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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 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.

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.

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

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 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.

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.

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

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].

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.

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.

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.

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.

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.

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 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.

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.