Pathophysiology

The normal intestine has a specific immune state in which the mucosa is usually unresponsive to luminal contents because of oral tolerance, as opposed to exposure to the same antigens subcutaneously or intramuscularly. This is regulated by anergic T cells or suppressor CD4 lymphocytes. In IBD, the key pathologic finding is infiltration into the lamina propia of immune cells, both related to the cellular response (macrophages, neutrophils, natural killer T cells) and the humoral response (T and B cells). Additionally, there is a high concentration of proinflammatory substances, such as tumor necrosis factor a (alpha) (TNF-a), cytokines, and interleukins. It appears that both in UC and CD, a genetic predisposition results in activation of the immune response by CD4 T lymphocytes, as a response to normal intraluminal content. Once initiated, this immune response is perpetuated by T cell activation. In a normal immune response, as the infection subsides, anti-inflammatory substances are secreted to regulate the reaction and avoid excessive tissue damage. In IBD, there is an imbalance between proand anti-inflammatory agents, and abnormal reaction continues uncontrolled [1].

Some authors suspect an infectious etiology for IBD. There have been several agents implicated in the abnormal activation of the immune system. These include pathologic organisms such as

Salmonella sp., Shigella sp., Campylobacter sp., Clostridium difficile, Mycobacterium paratuberculosis, and Escherichia among others. This idea is supported by the improvement of symptoms by different nutritional plans and with agents that modify the normal intestinal flora (antibiotics, antihelminths). Psychosocial factors, such as stress, are also related to exacerbation of the symptoms.

Various genes have been implicated in the development of IBD. The gene NOD2 is a sensor of peptidoglycans present in bacterial cell walls and has been associated especially with Crohn’s disease. ATG16L1 and immunity-related GTPase M protein (IRGM) have also been associated with CD. Alterations in the interleukin-10 (IL-10) receptor have been related to CD, whereas mutations in the IL-23 receptor and signaling pathway have been related to both UC and CD.

Clinical Presentation

Ulcerative Colitis

Patients usually present with diarrhea, rectal bleeding, tenesmus, passage of mucus or pus, and abdominal pain. The severity is very variable, and the symptoms usually last from weeks to months. Complications range from massive hemorrhages (1% of patients) to an acute dilation of the transverse colon, referred to as “toxic megacolon,” which may end up in a perforated bowel and the need for urgent surgery. About 5–10% of patients develop strictures and rarely present anal fissures or abscesses.

Crohn’s Disease

This form starts with similar symptoms of chronic bowel inflammation. However, as opposed to ulcerative colitis, CD progresses to one of two patterns of disease: a fibrostenotic-obstructing pattern or a penetrating-fistulous pattern. Complications include a small number of free perforations (1–2%) but very frequent fistula formation. Additionally, 10–30% of patients will develop pelvic or intraabdominal abscesses, usually needing resection of the compromised bowel portion. They can also present with severe hemorrhage, malabsorption, and severe perianal disease.

Between 25% and 36% of patients have extraintestinal complications, which include cutaneous, articular, hepatobiliar, and ocular manifestations [4]. Sacroiliitis (14%) and peripheral arthritis (10.7%) were found to be the most frequent in a case study [5].

Ocular Manifestations

Ocular manifestations occur in approximately 6% of patients [6] with CD and 8% of patients with UC [7]. The patient with ocular involvement usually either has a diagnosis of IBD or has gastrointestinal symptoms. However, it is important to know that ocular manifestations may be the presenting feature of the disease [8]. Ocular involvement can be independent of the severity of the disease at the time [9] and usually presents within the first years of diagnosis [6].

Most of the ocular symptoms in IBD relate to the anterior segment and ocular surface: mainly anterior

Fig. 16.1 (a, b) A 25-year-old female complains of decreased visual acuity in both eyes. Past ophthalmological history was positive for anterior uveitis in both eyes, which resolved with topical steroids. At examination, visual acuity was 20/50 in both eyes. Fundus examination disclosed nonactive, confluent, plaque-like lesions involving the macula in both eyes. The patient was lost for follow-up.

(c, d) Fluorescein angiography shows early hypofluorescent lesions with late hyperfluorescence and staining in both eyes. (e, f) Five years later, the patient returned with a diagnosis of Crohn’s disease. Visual acuity was 20/25 in both eyes. Fundus examination showed nonactive lesions in both maculas. (g, h) Fluorescein angiography confirmed nonactive lesions in the macula in both eyes

uveitis, conjunctivitis, corneal ulcers, and episcleritis [6]. The most frequent ocular manifestation is anterior uveitis, often coinciding with acute gastrointestinal symptoms. It usually presents as a mild anterior nongranulomatous uveitis (60% of the cases), but it can present as panuveitis or retinal vasculitis in up to 30% of the time [10]. In patients with IBD, the presence of uveitis is closely related to HLA-B27 and the appearance of erythema nodosum and seronegative arthritis [11]. Women are at much higher risk of developing uveitis in IBD [9]. Episcleritis has been reported in up to 29% of patients, often related to the severity of the disease,

resolving when the underlying cause is treated [12]. Scleritis has been reported in up to 18% of the cases with much more serious consequences [10, 12].

Posterior Segment Lesions

There have been several reports of IBD associated with vitritis and retinitis, often with papillitis [13, 14]. Posterior uveitis was as frequent as 10% in one case series [15]. Features of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (Fig. 16.1a–h) have been described, mainly consisting of choroidal infiltrates responsive to steroids and patches of choroidal inflammation associated

with serous retinal detachments [16]. Posterior scleritis has also been described associated with choroidal infiltrates and retinal detachment [12]. Other manifestations include central serous chorioretinopathy, multifocal choroiditis [17], serpiginous choroidopathy [18], retinitis, macular edema, and retinal telangiectasias.

Retinal vascular disease has also been described, mainly branch retinal artery occlusion [19], central retinal artery occlusion, retinal vasculitis [20] (Fig. 16.2a, b, c), and ischemic optic neuropathy [21]. These events have been attributed to a likely prothrombotic state caused by activation of the coagulation cascade. Secondary retinal neovascularization has also been described [22].

Treatment of Ocular Manifestations

Patients with uveitis, scleritis, and other anterior segment inflammation usually respond to steroids— either topical, periocular, or systemic. In some cases,

the inflammation is resistant to steroids, in which case other immunosuppressive medications should be used. Patients with uveitis and HLA-B27 usually have a more severe disease, less responsive to steroids [23].

For posterior segment inflammation, systemic steroids are the initial therapy and may require use of long-term immunosuppressant “steroid-sparing agents.” Inflammation may subside with resection of the affected bowel segment, although ocular inflammation is not an indication for surgery.

Steroid-sparing agents such as azathioprine, mycophenolate, and methotrexate may need to be used chronically, although special attention needs to be paid to their multiple serious side effects (bone marrow depression, pancreatitis, hepatitis, hepatic fibrosis, opportunistic infections). Cyclosporine and tacrolimus are T cell inhibitors that have been used in cases of both uveitis and scleritis [24, 25].