Rare Extraintestinal Manifestations of Inflammatory Bowel Disease

Extraintestinal manifestations of inflammatory bowel disease (IBD) can be found in 21% to 36% of the affected patients. 1,–5 Virtually every organ system may be involved. Extraintestinal manifestations of IBD can be divided into 3 groups. 2 The first group affecting the skin, joints, eye and mouth includes preferably patients with colonic disease. In these patients the activity of the extraintestinal manifestations often parallels the activity of the underlying luminal disease. The second group comprises extraintestinal manifestations that occur secondary to complications of the underlying disease, mostly in patients with Crohn’s disease. These manifestations include kidney stones, obstructive uropathy, gallstones, or malabsorption. The third group includes all manifestations that cannot be placed into 1 of the first 2 groups. This review focuses on rare extraintestinal manifestations of IBD. If one defines extraintestinal manifestation as expression of the same underlying pathogenetic process that triggers IBD, it may often be difficult or even impossible to distinguish the coincidental occurrence of a disease from a really linked extraintestinal manifestation. This is even more difficult the rarer the event occurs. Rare extraintestinal manifestations in IBD may formally be divided in 1 rarely occurring alterations in frequently involved organ systems and 2 rarely affected organ systems (Table 1). Rare Extraintestinal Manifestations Rare Extraintestinal Manifestations Cutaneous disorders associated with IBD occur in about 15% of patients. 2 The most common dermatologic manifestations are erythema nodosum and pyoderma gangrenosum. The prevalence of erythema nodosum in patients with IBD is 10% to 20%. 2,6 Pyoderma gangrenosum can be found in 1% to 10% of IBD-patients—more often in association with ulcerative colitis than with Crohn’s disease. Psoriasis occurs in an increased frequency (about 10%) in Crohn’s disease patients compared with the general population. 7,8 Rare dermatologic manifestations in IBS are Sweet’s syndrome, epidermolysis, bullosa acquisita, and metastatic Crohn’s disease. Sweet’s syndrome, first described in 1964, is characterized by four cardinal features: fever, leukocytosis, tender red plaques, and histologic findings of a neutrophilic infiltrate with leukocytoclasis. These features led to the alternative term: acute febrile neutrophilic dermatosis. The cutaneous lesions involve the arms, legs, trunk, hands, and face. Associated systemic involvement include arthralgia or arthritis in more than 60%, fever in about 50%, and eye involvement (conjunctivitis, iridocyclitis) in about 40% of the patients. Women are affected much more frequently than men (86% in a study on 29 cases). 9 Sweet’s syndrome is associated with an underlying disease like cancer, lymphoma, or IBD in the majority of patients. Usually the appearance of Sweet’s syndrome in IBD patients parallels the gastrointestinal disease activity, but Sweet’s syndrome preceding IBD has been described. 10 Sweet’s syndrome and pyoderma gangrenosum have been noted successively in the same patient. 11 Furthermore, both diseases have been described in a similar range of conditions including leukemia, myeloma, and IBD. Most cases of Sweet’s syndrome show a response to systemic treatment with corticosteroids. 12 In 1 case with partial response to steroids, metronidazole was effective. 10 Epidermolysis bullosa acquisita (EBA) is an autoimmune disease manifesting as skin blistering and scarring. It may also involve the mucosae. EBA is characterized by autoantibodies of the IgG-isotype to type VII—collagen. Systemic diseases are often associated with EBA, Crohn’s disease, with 25% being the most frequent. 13 Recently it was shown, that the 290 kDa type VII collagen α-chain—the EPA-autoantigen—can not only be detected in the skin, but also in the colon of normal individuals. Antibodies to this antigen could be detected in 13/19 Crohn’s disease patients and 4/31 ulcerative colitis patients, but not in controls (RA patients and healthy people). 14 EBA may present only as a GI-disease without cutaneous involvement as has been shown in a case with localized EBA of the esophagus without skin involvement. 15 This case resembles that of a child who developed esophageal stenosis as an extracutaneous form of dystrophic epidermolysis bullosa because of compound heterozygosity mutations in the COL7A1 gene encoding collagen VII. 16 Metastatic Crohn’s disease (MCD) is a rare complication of Crohn’s disease with the features of cutaneous involvement, noncontiguous with the GI-tract. The diagnosis of MCD is based on the identical histologic appearance to Crohn’s disease, including non-caseating granulomas. 17 Other histologic findings include necrobiosis and granulomatous perivasculitis. 18 The cutaneous lesions mostly appear as ulcerating nodules which usually occur in skin folds of the anterior abdominal wall and submammary areas. Other areas of manifestations include vulva, penis, retroauricular skin folds, ankles, and knees. The bronchial tree and the pancreas may be involved (see below). 19,–22 The skin lesions usually parallel active disease in the GI-tract, but may precede the diagnosis of Crohn’s disease. Treatment is based on anecdotal reports. Corticosteroids seem to be effective in two thirds of treated patients, 23,–26 topical steroids produced a response in three reported cases. 27,28 While azathioprine worked in 2 out of 4 cases, 23,29 cyclosporine and antibiotics did not show significant benefit in treating MCD. Infliximab was used with good success in 2 cases with MCD presenting as non-healing perineal wounds after proctocolectomy. 30 The most common hematologic complication of IBD is anemia resulting from iron, vitamin B12, or folate deficiency. The incidence of thromboembolic events ranges from 1.3% to 3.9%. The hypercoagulate state in patients with IBD most often manifests as deep vein thrombosis or pulmonary embolism. The myelodysplastic syndrome may represent a very rare extraintestinal manifestation of IBD. 31,–33 The frequency of MDS in IBD seen in a referral center was 0.17% in about 15.000 patients, although this figure does not mean a true prevalence or incidence rate. 34 Several features support the notion that MDS in IBD represents an association rather than a coincidental occurrence: MDS in IBD occurred simultaneously in one third to half of the patients 34,35; they were relatively old for Crohn’s disease, but young for MDS, and Crohn’s disease patients showed a high frequency of colonic involvement. While a preponderance of Crohn’s disease (15 of 17 cases) was found in one series, MDS cases were more or less equally distributed between Crohn’s disease and ulcerative colitis in another. 34,35 The pathogenesis of the possible association MDS-IBD remains unclear, but several hypotheses have been discussed. 35,36 In MDS, especially CMML, high cytokine production like IL-1, IL-6 and TNFα can be found. 37 These cytokines, especially TNFα, have been shown to be of importance in the pathogenesis of Crohn’s disease. 38 An infectious participation has been suggested in the pathogenesis of IBD. 39 Abnormal neutrophils and/or lymphocytes found in patients with MDS may predispose them to chronic bowel infections and increase the risk of IBD. 35,36 Finally, IBD in these patients may represent an extrahematologic manifestation of MDS as some patients with MDS may show a systemic, vasculitic-like syndrome of fever, arthritis, cutaneous vasculitis, and neuropathy. 40,41 It has been suggested that Crohn’s disease may be a vasculitis involving mesenteric blood vessels that feed the gut. 42 MDS should be taken into account especially in IBD-patients who show a normochromic, normocytic anemia, because many of the MDS-IBD patients first were persistently anemic for at least one year before the diagnosis of MDS could be made. 34 Musculoskeletal diseases are the most common extraintestinal manifestations found in patients with IBD. These diseases can be divided in rheumatologic disorders and metabolic bone abnormalities. Peripheral arthropathy occurs in 5% to 20% of IBD patients the risk increasing with the extent of colonic disease. Axial arthropathy occurs less frequently in 3 % to 5% of patients. 1,–5,43 In contrast to peripheral arthropathy, it does not parallel GI-disease activity. Metabolic bone disorders—osteoporosis and osteopenia—are very common occurring in 23% to 59% of patients with IBD. 44,–47 Osteomalacia, usually caused by vitamin D deficiency, can be found in 1% to 5% in patients with Crohn’s disease. A very rare, but clinically important extraintestinal manifestation is osteonecrosis. Osteonecrosis—also termed aseptic necrosis of bone or osteochondrosis dissecans— involves multiple joints in most cases. The femoral heads are most frequently involved, followed by the femoral condyles, the proximal humerus and talus. 48 The prevalence rate in Crohn’s disease is less than 0.5%. 49 Patients present with pain aggravated by motion and eventually swelling of joints. The disease is bilateral in most cases. Just as with other underlying diseases (rheumatoid arthritis, systemic lupus erythematosus, malignant lymphoma, renal homotransplants, etc.) the development of osteonecrosis in IBD is often associated with corticosteroid therapy. But this is not a prerequisite, some cases have been described without steroid therapy. 49,50 Patients are younger (median 28 years) and the dose and duration of corticosteroid treatment is lower than in other diseases associated with osteonecrosis. 51 Those with severe GI-disease may be more susceptible. The concurrent use of total parenteral nutrition with corticosteroid treatment seems to place the patients at an additional risk for osteonecrosis. 52 Data on the relationship between the dose or the duration of corticosteroid therapy and the development of osteonecrosis are conflicting. While some authors described a positive correlation to duration of treatment, to high cumulative and high peak doses, other studies have not shown such an association. 53,–57 The mechanism of steroid induced osteonecrosis is unclear. Various theories have been proposed. 58,59 It has been suggested, that an underlying multisystem illness impairs osteoblast function and thus increases the susceptibility to osteonecrosis by a second hit such as corticosteroid therapy (accumulative cell stress theory). 60 For diagnosis, bone scans are helpful in most cases, whereas radiographs may not show abnormalities in the early phase of the disease. 51 Magnetic resonance imaging has been shown to be very sensitive for the detection of early disease. 54 The treatment of osteonecrosis is unsatisfactory. In the early stage of the disease treatment is more likely to be successful. The traditional treatment is protected weight bearing. Core decompression, eventually in combination with bone grafts are surgical alternatives for the early stages. 54 In late stages arthroplasty is the mostly used therapeutical method. 61 Nephrolithiasis, obstructive, uropathy, and fistulization to the urinary tract are common manifestations, occurring in 6% to 23% of patients with IBD. 62 Secondary amyloidosis involving the kidney is a rare but serious extraintestinal manifestation of IBD. Most of patients of amyloidosis associated with IBD presents with proteinuria, renal dysfunction, and uremia. The literature has reported approximately 100 cases. Two large single center studies, one with 16 cases of amyloidosis in 3.050 patients over 25 years, one with 18 patients with amyloidosis in a referral cohort of approximately 500 patients registered over 25 years showed a male preponderance of about 3:1. Amyloidosis occurs 10 to 13 times more often in Crohn’s disease than in ulcerative colitis and about 4 times more often with Crohn’s disease of the colon than with isolated small bowel disease. 63,64 In one unselected series, amyloidosis occurred in 0.9% of patients with Crohn’s disease and 0.07% of patients with ulcerative colitis. 63 About two thirds of the patients with amyloidosis show suppurative complications such as abscesses or fistulas. In the majority of patients other extraintestinal manifestations such as eye or skin involvement can be found. 63,64 In one study, published recently in this journal, the time from diagnosis of IBD to the diagnosis of amyloidosis ranged from 0 to 28 years (median time 4 years). In about one third of the patients, amyloidosis was present at the time of diagnosis of IBD. 64 Diagnosis can be made with liver, rectal, or renal biopsy. Treatment options include the use of colchicine and renal transplantation. 65,66 Despite the use of transplantation overall survival rate after 15 years is reduced to 60%. 64 The association of IBD with neurologic manifestations is thought to be rare and often discussed as controversial. In a recently published study, neurologic complications of IBD were described in 3% of a series of 638 patients. 67 Four groups of site involvement could be identified: peripheral neuropathy, myopathy, cerebrovascular disease, and myelopathy. The literature has reported about 50 cases of peripheral neuropathy in association with IBD. In about 10% of these cases it manifests as an acute inflammatory demyelinating polyradiculopathy (AIDP), the Guillain-Barré syndrome. 67,–69 A preponderance of ulcerative colitis in these cases has been observed. 67 This is in contrast to polyneuropathy which seems to be associated mainly with Crohn’s disease. 70,–72 In view of the occurrence in parallel of cutaneous vasculitis, the demonstration of circulating immune complexes and the therapeutic efficiency of plasma exchange, it has been suggested that the underlying pathogenetic process in these cases is vasculitis. 70 The same pathogenetic mechanism was discussed in a patient with mononeuropathy multiplex with ulcerative colitis, in whom neurologic symptoms correlated well with the disease activity of the colitis. 73 One important differential diagnosis to keep in mind in these cases is peripheral neuropathy due to metronidazole treatment. 74 In most cases, a sensory PNP can be found, especially in children. Risk factors are long-term treatment with metronidazole and a cumulative dose of >30 g of metronidazole. 75 Symptomatic disease develops in about half of the patients in whom abnormal neurophysiologic measurements can be obtained. Complete resolution or improvement after stopping of metronidazole therapy is frequent, but persistent peripheral neuropathy has been described also. 74 In the largest series published, myopathy was found in 3 of the 638 patients investigated. 67 Although other cases on dermatomyositis associated with IBD have been reported, a coincidental occurrence cannot be ruled out. 76 On the other hand, in 1 case a severe polyneuropathy in a patient with Crohn’s disease was associated with a granulomatous myositis with epithelioid granuloma, which makes myopathy as an extraintestinal manifestation of Crohn’s disease highly probable. 71 Other isolated cases of inflammatory and granulomatous myopathies support this notion. 77,–82 Cerebrovascular involvement is documented in 0.12% to 4% of patients with IBD. 83,84 In many cases this may be the neurologic manifestation of a thromboembolic event. Thromboembolic events in IBD are quite common, ranging from 1.3% to 3.9% in retrospective studies and mainly manifest as deep vein thrombosis or pulmonary embolism. 84,85 The neurologic manifestations include sinus vein thrombosis, transient ischemic attacks, strokes, retinal vein occlusion, medullary thrombosis and others. 67,84,86,–88 They occur at any age, equally in both sexes, and show a correlation with disease activity of IBD. 86,89 Several case records have suggested that cerebral vasculitis may be a neurologic extraintestinal manifestation of IBD. 90,91 In this connection it is noteworthy that focal white matter lesions have been found in high frequency in the brain of neurologically asymptomatic patients with IBD by magnetic resonance imaging. 92 The frequency was as high as that found in systemic lupus erythematosus or multiple sclerosis. Since the patients studied were all below 40 years of age a vasculitic rather than an arteriosclerotic origin was suggested. Recently a case of symptomatic microangiopathic neurologic disease (white matter lesion) that started shortly before the manifestation of ulcerative colitis and aggravated with gastrointestinal disease activity was reported. 93 To date, only 7 cases of myelopathy associated with IBD have been published. 67,94,95 These cases may as well be coincidental, since malabsorption induced myelopathy or an unusual reaction to the medication may be involved. 96,97 One important differential diagnosis may be the direct involvement of the myelon by abscess formation due to fistulation as has been described in a patient with Crohn’s disease. 98 Several cases have been reported on the occurrence of multiple sclerosis (MS) and IBD, mainly Crohn’s disease, in the same patient. 99,100 Likewise, an association between MS and ulcerative colitis has been found in a study of 2.261 women who underwent total colectomy in the UK. 101 Furthermore, family studies from Southern Alberta (USA) and British Columbia detected an association of IBD and MS in 17 and 27 families, respectively. 102,103 Recently, a formal epidemiological survey performed in Olmsted County, Minnesota (USA) looked for the prevalence of MS in population-based cohorts of patients with Crohn’s disease and ulcerative colitis. The observed prevalence of MS at onset of IBD was 3.7 times higher than expected. 104 Thus, MS and IBD are coexisting both within families and within individuals. Focal white matter lesions found in patients with IBD and neurologic symptoms have been linked to MS. 105 However, since the onset of neurologic symptoms in most of the investigated patients was remote from and equally likely to precede or to follow the onset of IBD, a coexistence of the two diseases based on genetic links rather than an extraintestinal manifestation of IBD has to be considered. Several groups have shown unequivocally that lung function is subclinically disturbed in IBD in about 40% to 60% of the patients. 106,–110 In all performed a of the for was found. While some authors could not in pulmonary function between IBD patients and showed that parallel with more of lung function lung function seems to be on disease activity, being with active significant pulmonary disease on the other is The incidence of lung disease remains to be have to on case records and small series, the largest of which comprises patients. In most cases pulmonary extraintestinal manifestations seem to follow the onset of IBD. In one series, symptoms followed the onset of IBD by an of 12 years 4 to years). In most cases, IBD was The majority of the patients disease involvement seems to in patients with ulcerative colitis and with Crohn’s disease. disease and chronic are associated with ulcerative colitis, occurs in with Crohn’s disease. with pulmonary and and are associated with IBD. The of pulmonary involvement in IBD are in involvement in IBD may be divided into disease, lung disease, and lung disease induced by used in IBD. of in IBD of in IBD and have all been described in association with IBD. the high prevalence of chronic in the general it may be difficult to chronic as an extraintestinal manifestation of IBD. However, most pulmonary in IBD occur with disease, a parallel of bowel and bronchial symptoms has been observed. most of the patients affected were which is unusual with chronic involvement occurred after in some it seems to occur even more often after Furthermore, involvement after colectomy to be more severe than without This has been as a of the inflammatory process from the bowel to the bronchial both organ systems a common the gut. In Crohn’s disease an involvement of the bronchial tree by a granulomatous process has been described in at least 2 cases. This may be as a form of metastatic Crohn’s disease (see similar to 1 case in the with involvement of the that to be associated with and lupus is also associated with IBD. In some cases of autoantibodies could be and occurred early in the disease but were for a Most patients very well to or systemic may be used in cases. occurs rarely in patients with association with IBD in the cases described remains like or may lung disease like with or pulmonary and (see below). the between induced disease and lung disease associated with IBD may be very difficult in some However, in patients with IBD developed before the onset of in with the onset of IBD and in patients not in these cases and IBD are associated or represents an extraintestinal manifestation of IBD is at has been associated with the of However, in the largest series published by in 3 cases, a for could be ruled out. the of these authors that should be as extraintestinal manifestation of IBD. in IBD About 50 cases of lung disease have been reported in the disease induced by manifests as in half of the cases, followed by lung disease and symptoms are and Most patients could be by without a for steroid treatment. However, have been reported. The of is to Thus, pulmonary events to are less frequently found than with Most case records on which may be of lung disease after and use of has been described. with in a patient with has been described in 1 resulting in the same lung disease as the first