Case 5 -

Crohn's Ileitis with Superimposed Giant Cell Arteritis Involving Mesenteric Arteries John Hart University of Chicago Hospitals Chicago, IL

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Clinical History The patient is a 15-year-old male with a several year history of Crohn's disease. The patient has been treated in the past with steroids and infliximab. Recently obstructive symptoms led to a small bowel follow through, which revealed a tight stricture in the terminal ileum. An ileocecectomy was performed. Gross examination of the specimen documented a 3 cm stricture of the distal terminal ileum with linear ulcers and effacement of the usual mucosal fold pattern. The cecum and appendix were grossly unremarkable. A representative section from the ileal stricture is provided for review. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 - Low power of ileal section revealing thickened wall and transmural inflammatory changes typical of Crohn's disease Case 5 - Figure 2 - Medium power of above highlighting mucosal architectural distortion and submucosal fibrosis. Case 5 - Figure 3 - Medium power of above to demonstrate neuronal hyperplasia, and serosal granulomas and lymphoid follicles. Case 5 - Figure 4 - Low power of medium sized mesenteric artery included in the ileocecetomy specimen, reveal occusion due to intimal hyperplasia and fibrosis. Case 5 - Figure 5 - Medium power demonstrating active arteritis. Case 5 - Figure 6 - High power reveal multinucleated giant cells and disruption of the elastica. Case 5 - Figure 7 - Another mesentery artery exhibiting active giant cell arteritis and surrounded by granulomatous inflammation. Case 5 - Figure 8 - Another mesenteric artery exhibiting active giant cell arteritis. Histologic Findings Sections reveal classic histologic features of Crohn's disease, including mucosal ulceration in a background of mucosal architectural distortion, submucosal fibrosis, neuronal hyperplasia, scattered granulomas, and transmural inflammatory changes. In addition, there is a giant cell arteritis affecting mesenteric arterial branches, with disruption of the elastica, intimal hyperplasia and fibrosis, and dystrophic microcalcifications. However, ischemic changes are not evident in the overlying bowel. Diagnosis: Crohn's ileitis with superimposed giant cell arteritis involving mesenteric arteries. Discussion Crohn's Disease and Vasculitis Patients with Crohn's disease can develop a wide range of extraintestinal manifestations, including vasculitis. In addition, a number of vascular changes have been described within the intestine itself in Crohn's disease, some of which are thought to be important in the pathogenesis of the disorder. Patients with Crohn's disease sometimes present initially with signs and symptoms due to vasculitis involving an extraintestinal site (skin, retina, skeletal muscle), or develop vasculitis in one of these organs after the diagnosis of Crohn's is established [1, 2, 3, 4]. A diagnosis of primary systemic vasculitis is not warranted in such cases because: 1) multiorgan involvement by the vasculitic process is not evident, and 2) the gastrointestinal disease is typical of Crohn's disease, with no evidence of vasculitis or ischemic changes. The histologic features of the vasculitis involving the extraintestinal site are variable, as is the size of vessel involved. Treatment of the Crohn's disease is usually effective in suppressing the vasculitic component as well. Laboratory evaluation in patients with colonic Crohn's disease not infrequently reveals an elevated titer of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). The specificity of these autoantibodies in terms of a neutrophil organelle or protein target are not well studied, and appear to vary among different patient populations. These autoantibodies should be clearly separated from the cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCA) that are almost always found in elevated titer in patients with small vessel systemic vasculitis [5, 6, 7]. These autoantibodies, which are known to be directed against either myeloperoxidase or proteinase 3, are almost never present in elevated titer in patients with idiopathic inflammatory bowel disease (IBD). Nonetheless, in both systemic vasculitis and IBD the formation of the anti-neutrophil autoantibodies is believed to be related to the apoptotic destruction of these cells, and the antibodies may in fact play a role in the pathogenesis of these disorders. System Vasculitis Misdiagnosed as Crohn's Disease Many patients with systemic vasculitides originally present with symptoms and signs that closely resemble those typical of inflammatory bowel disease. Because gastrointestinal involvement by vasculitis often is segmental, with intervening "skip areas" of normal bowel, a close radiographic and histologic resemblance to Crohn's disease is also possible. In particular, Behçet's disease, polyarteritis nodosa, and microscopic polyangiitis must be considered in patients diagnosed with Crohn's disease with atypical clinical, radiographic or histologic features [8]. The proper recognition of gastrointestinal vasculitis may be difficult because the affected vessels are difficult to visualize radiographically (owning to their small size) and are difficult to access by biopsy (due to their submucosal location). A recent study reported on ten children who presented with abdominal pain, weight loss, diarrhea (bloody in six) and exhibited patchy mucosal ulceration by endoscopy [9]. Biopsies were read as consistent with inflammatory bowel disease in five of the patients, and non-specific changes in the remaining five. Further work-up over the next 2 to 24 months revealed either radiographic or pathologic evidence of systemic vasculitis (polyarteritis nodosa in nine and microscopic polyangiitis in one). The authors emphasized the importance of visceral angiography in the proper diagnosis of systemic vasculitides, but noted that the classic diagnostic changes may not be present in patients already treated with immunosuppressive drugs for presumed IBD. Instead, more subtle (non-aneurysmal) changes must be regarded as consistent with vasculitis by the radiologist. Biopsies of other organs can also be very helpful in documenting vasculitis (skin, kidney, skeletal muscle). Gastrointestinal involvement by Behçet's disease can closely resemble Crohn's disease radiographically (focal mucosal ulcerations most commonly of the ileocecal region, stricture formation) and histologically (focal transmural inflammatory changes, granulomas (?), submucosal fibrosis). The extraintestinal manifestations of Behçet's disease (oral and genital ulcers, eye changes etc.) are the key to proper diagnosis [10]. Giant Cell Arteritis, Takayasu's Arteritis and Crohn's Disease Giant cell arteritis and Takayasu's arteritis are two of the three known systemic vasculitides that primarily affect large arteries (Kawasaki's arteritis is the third). These two forms of vasculitis are histologically indistinguishable, and the differential diagnosis rests upon the age at presentation, the site(s) of involvement, and the presenting symptoms [11, 12]. In general, cases are classified as Takayasu's arteritis when the patient presents at an age of less than 40 years, and when there are symptoms and radiographic evidence of involvement of the major branches of the proximal aorta. Giant cell arteritis is diagnosed primarily in older individuals with involvement of large cranial arteries (especially the temporal artery). Involvement of the gastrointestinal tract by giant cell arteritis or Takayasu's arteritis is rare, occurring in less than 1% and about 10% of cases respectively [8, 13, 14]. Gastrointestinal involvement is caused by active vasculitis of large mesenteric vessels resulting in ischemia, and is usually diagnosed by angiography. An association between intestinal Crohn's disease and large vessel arteritis has been noted sporadically in the literature since the early 1970s, usually in the form of individual case reports or small series, for a total of about 50 patient. In most of these cases the vasculitis is classified as Takayasu's arteritis [15, 16, 17, 18, 19, 20, 21, 22], since the patients are diagnosed before the age of forty years, and exhibit symptoms and radiographic evidence of involvement of branches of the proximal aorta, as well as mesenteric vessels. In about half of the cases the arteritis is diagnosed first, while in the other half the patient has an established diagnosis of Crohn's disease and then develops vasculitis involving the aorta or its large proximal branches. Interestingly, gastrointestinal ischemia is not described in any of these cases, and in fact the mesenteric arteries do not appear to be affected. Instead, the two disease processes appear to run separate courses and do not impact significantly on one another. There appears to be only one previously reported case similar to the patient discussed here, in which giant cell arteritis is documented histologically to involve mesenteric vessels supplying intestine affected by Crohn's disease [23]. In that report, as in the current case, there were no ischemic changes in the bowel and no symptoms of vasculitis involving the aorta or its major branches. Vascular Changes in Intestinal Crohn's Disease Although often overlooked today, granulomatous lymphangitis was highlighted as a key histologic feature in the early systematic descriptions of the microscopic pathology of Crohn's disease [24, 25, 26]. A landmark review published in 1954 of the experience of the New England Deaconess Hospital Department of Pathology concluded that "…the chief disease process is a progressive granulomatous lymphangitis. It affects and scleroses lacteals in the intestinal lamina propria … and similarly affects lymphatics in the intestinal submucosal, muscular, and subserosal layers [27]. All of these reports included photomicrographs demonstrating granulomas involving or impinging on dilated lymphatic channels. Emphasis of this histologic finding waned until 1991, when Wakefield et al, utilizing a perfusion fixation technique, again noted the close association of granulomas and vascular structures in the intestinal wall, and proposed that granulomatous vasculitis was an important element of the pathogenesis of Crohn's disease [28]. At the time these investigators were unsure if the granulomatous inflammation primarily affected arterial, venous, or lymphatic channels [28, 29], but subsequent studies have focused on the involvement of the lymphatics [30, 31]. Wakefield later developed an animal model of microvascular occlusion that recapitulated some of the histologic features of Crohn's disease, providing some additional evidence for a vasculitic component in the pathogenesis of the disease [32, 33, 34]. Subsequently Wakefield claimed that measles virus infection of endothelial cells could be responsible for development of the granulomatous lymphangitis and that atypical measles infection at an early age might even be the cause of Crohn's disease [35, 36, 37, 38, 39, 40, 41]. Other investigators have been unable to identify measles virus in intestinal tissues from Crohn's disease patients, and epidemiologic studies have failed to find convincing evidence that measles infection increases the risk for Crohn's disease [42, 43, 44, 45, 46]. Nonetheless, the observation that granulomatous vasculitis is a consistent feature of Crohn's disease is valid, although the significance and underlying cause remain elusive. Aphthous erosions and micro-ulcerations are regarded as among the earliest histologic features of Crohn's disease, and there is some evidence that microvascular damage leading to mucosal ischemia may play a part in the formation of these lesions. In situ fluorescent endoscopy has demonstrated subtle microvascular abnormalities in otherwise endoscopically normal mucosa in Crohn's patients [47], and perfusions studies have confirmed capillary wall damage beneath aphthous lesions [48]. Additional studies have documented pathologic changes in larger vessels beneath linear ulcers [49, 50]. Radiographic studies have also confirmed dimunition of blood flow to bowel segments affect by Crohn's disease [51]. However, all of the investigators involved in this area recognize that it is difficult to determine whether these vascular changes precede or are a consequence of the inflammatory changes that are occurring in the surrounding tissues. References Gudbjornsson B, Hallgren R. Cutaneous polyarteritis nodosa associated with Crohn's disease: report and review of the literature. J Rheum 1990; 17:386-90. Zlatanic J et al. Crohn's disease and acute leukocytoclastic vasculitis of skin. Amer J Gastroenterol 1996; 91:2410-3. Disdier P et al. 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