Inflammatory bowel disease (IBD), comprised mainly of Crohn’s disease and ulcerative colitis, is a chronic, inflammatory gastrointestinal disease of unknown etiology. The incidence of IBD peaks in early adulthood, although this trend is more evident in women [1]. Although the exact pathogenesis of IBD is unknown, environmental factors (microbial, dietary, allergic, et al.) and genetic susceptibility appear necessary for the development of the disease [2]. Further, the reduction of antigenic challenges early in life may play a role, as such exposures appear critical for the development of immune tolerance [3, 4]. Accordingly, IBD is most prevalent in the increasingly sterile environment of developed countries [3, 4]. However, the incidence of IBD is on the rise in developing countries, such as India, as demographic changes occur toward more relative affluence and sanitation and other public health measures improve [3].

While Crohn’s disease and ulcerative colitis are considered separate disease entities, patients often have common presenting symptoms, such as abdominal pain, diarrhea, hematochezia, and urgency [2]. Systemic symptoms, including fever, weight loss, and joint pain, are common [5]. A detailed history inquiring about these symptoms should be taken when approaching any patient with uveitis. Heightening the role of the ophthalmologist in assisting with diagnosis and management in these individuals, the ocular manifestations and complaints may precede the diagnosis of IBD on occasion.

In addition to the primary gastrointestinal manifestations, IBD is associated with several extraintestinal complications. Most commonly, these include arthritis, aphthous stomatitis, erythema nodosum, ankylosing spondylitis, psoriasis, pyoderma gangrenosum, primary sclerosing cholangitis, and uveitis [6, 7]. These extraintestinal manifestations may precede the gastrointestinal disease by years and some, including uveitis, have a course that may run independent of the gastrointestinal disease activity [6].

The prevalence of ocular complications in patients with IBD varies considerably, likely based upon differences in reporting and classification [2, 8]. When examining IBD patients prospectively for related eye disease, either symptomatic or silent, more than 40 % will have evidence of an ocular complication [9]. Approximately half of these complications are merely dry eye, which appears to be more prevalent among IBD patients as seen with numerous other autoimmune diseases [10]. Episcleritis is the most common non-dry eye-related ocular manifestation, affecting up to 30 % [2]. However, in many studies, uveitis is the most commonly reported ocular manifestation, presumably because episcleritis is often self-limited and not necessitating treatment [2]. The spectrum of eye disease though is broad. Other ocular manifestations of IBD include conjunctivitis, keratitis with or without peripheral ulceration, scleritis, episcleritis, scleromalacia perforans, retinitis, optic neuritis, orbital myositis, ocular myasthenia gravis, retinal artery occlusion, and retinal detachment [11–21]. In some cases, these ocular manifestations can occur concurrently with uveitis.

The reported occurrence of uveitis in patients with IBD varies, generally in the range of 2–12 % [6, 22–25], but may be significantly less common in pediatric patients with IBD [26]. Crohn’s disease appears to carry a higher risk of uveitis as compared to ulcerative colitis, more than 1.6-fold in a large, prospective cohort study [6]; however, the data regarding a differential incidence between the two subtypes of IBD are conflicting [27]. This relationship is further obfuscated by the fact that colonic or ileocolonic involvement in Crohn’s disease patients appears to increase the risk of ocular inflammation (uveitis, episcleritis, and scleritis) by more than eightfold [5, 28]. Women with IBD have a higher incidence of uveitis [25, 29]. Additionally, there is a strong link between sacroiliac joint abnormalities, arthritis, HLA-B27 positivity, ANCA positivity, and the development of uveitis in IBD patients [22, 25, 29, 30]. Other genetic risk factors have been identified; ulcerative colitis patients with the HLA-DRB1*0103 allele more frequently suffer from associated uveitis and arthritis [31]. These associations, particularly HLA-B27 positivity, can be particularly important since ocular disease course and treatment response can vary based on the presence of this genetic profile [32].

While there is a strong association between IBD and uveitis, there is discordance between the severity of bowel disease and uveitis [22, 25]. Uveitis can occur during active gastrointestinal flares or during periods of remission [28, 33]. In some cases, uveitis may precede the diagnosis of IBD by several years [28, 34–36].

As for most uveitides of other causes, a careful assessment of ocular symptoms can help predict the location of uveitis that will be found on ocular examination. Redness, photophobia, pain, and decreased vision suggest an anterior uveitis, while decreased vision with floaters often indicates intermediate pathology. Although rare, scotomata could be suggestive of posterior involvement.

Overall, the most common type of uveitis associated with IBD is an acute, recurrent anterior uveitis, often bilateral [29]. This presentation accounts for more than 60 % of IBD-associated uveitis [37]. Typically, this is a nongranulomatous, low-grade inflammation although there have been reports of granulomatous uveitis as well as hypopyon associated with IBD [28, 38, 39]. Less commonly, patients with an anterior presentation may have a monophasic episode of nonrecurrent anterior uveitis, but this is estimated to occur in roughly ten percent of patients with IBD-associated uveitis [37]. In comparison to the uveitis associated with ankylosing spondylitis, a disease closely related to and often difficult to differentiate from IBD, the uveitis associated with IBD is more likely to be bilateral, posterior, insidious in onset, and chronic [29].

While anterior uveitis accounts for a majority of IBD-associated uveitis, up to 10–30 % percent of IBD patients with uveitis have posterior or panuveitis, sometimes mimicking other disease entities [37]. Many of these patients will have an associated retinal vasculitis [8]. Rarely, intermediate uveitis with snowbanks has been observed [34]. Multifocal choroiditis has been described in Crohn’s disease; similarly, numerous cases of choroidal inflammation with associated serous retinal detachments have been reported [8, 21, 23, 40]. Acute multifocal placoid pigment epitheliopathy has been described [41]. Additionally, ulcerative colitis has been associated with subretinal fibrosis and uveitis syndrome in one report [42]. Although these cases are rare, they illustrate the broad spectrum of uveitis, including posterior uveitis, which can be associated with IBD.

In most instances, ocular symptoms prompt presentation to an ophthalmologist for evaluation and treatment of uveitis. As a result, there are currently no screening guidelines for uveitis in patients with IBD [43]. More so, ophthalmic symptoms in patients with IBD have a low positive predictive value for identifying true ocular inflammatory disease (uveitis, scleritis, keratitis, et al.) [44]. However, it is possible that subclinical anterior uveitis may be more common than originally believed, particularly in children. Multiple prospective case series have described an asymptomatic anterior uveitis in pediatric patients with IBD, particularly Crohn’s disease [45–47]. Asymptomatic anterior uveitis was seen in 6.2–16.7 % of patients with Crohn’s disease in these cohorts [45, 47]. In many cases, inflammation was transient and subsided without treatment, suggesting that routine screening for uveitis among pediatric IBD patients is likely unnecessary.

When considering treatment for uveitis associated with IBD, the ophthalmologist must inquire about the activity of the underlying gastrointestinal disease and any concurrent, systemic anti-inflammatory therapy. If the patient has active bowel disease currently not under treatment, the management plan should be coordinated with the patient’s primary gastroenterologist and/or rheumatologist in order to find a regimen that minimizes risk and optimizes benefit in controlling inflammation in both organ systems.

As with other autoimmune or autoinflammatory uveitides with or without systemic association, most uveitis specialists employ a step-up approach to treatment, commencing with less potent and ideally, less risk laden, medications first and saving more efficacious, and potentially more toxic, therapies for nonresponders. At the same time, initial management of IBD-associated uveitis is guided by the location of inflammation. Since most patients present with anterior uveitis, many will respond to topical corticosteroids and cycloplegics alone. Occasionally, local steroid injections may be needed. Depending on the course of the anterior uveitis (acute recurrent, acute monophasic, or chronic), the ophthalmologist can determine whether or not the topical steroid can be tapered to discontinuation or maintained at an infrequent, suppressive dose. However, the course of IBD-associated anterior uveitis may recur with excessive frequency or a chronic anterior uveitis may not be controllable with low-dose topical steroid. As a result, patients may require oral steroid therapy with subsequent transition to immunosuppressive treatment, if unable to taper the oral steroids to 5 mg of prednisone (or equivalent) or less daily or if prolonged steroid treatment leads to a significant number of intolerable side effects. This is more common in patients with HLA-B27 positivity [32]. Patients presenting with posterior uveitis generally require initial treatment with oral steroids and often will need to transition to steroid-sparing agents when the course of uveitis is persistent.

Several options are available for steroid-sparing immunosuppressive therapy for IBD-associated uveitis. In keeping with the step-up approach, the most common drugs initially employed are antimetabolites, namely methotrexate, azathioprine, and mycophenolate mofetil. Methotrexate and azathioprine, specifically, have demonstrated effectiveness in suppressing uveitis in the setting of IBD, though the data are limited [32, 48]. Extrapolating from an 82 % success rate in suppressing noninfectious uveitis and other ocular inflammation, mycophenolate mofetil is similarly routinely used [49]. Currently, there are no studies comparing the relative efficacy of these medications for uveitis associated with IBD.

Less commonly, T cell inhibitors, such as cyclosporine and tacrolimus, have been used as steroid-sparing treatment for uveitis in IBD patients, although the side effect profile, namely nephrotoxicity and hypertension, can limit the tolerability of these medications [8, 32]. These may be combined with an antimetabolite for refractory uveitis or used as monotherapy. For truly refractory cases of sight-threating uveitis, alkylating agents, such as cyclophosphamide and chlorambucil, have been employed in patients with IBD [32].

Though relatively newer to the scene, TNF-alpha inhibitors have proven remarkably successful in controlling both ocular and gastrointestinal inflammation in IBD, even in the setting of highly refractory cases [8, 50, 51]. In particular, infliximab has demonstrated efficacy in treating the extraintestinal manifestations of Crohn’s disease, including acute and recurrent uveitis, as well as gastrointestinal manifestations refractory to other treatment [52–54]. Paradoxically, infliximab has been implicated as a cause of anterior uveitis in a patient with ulcerative colitis [55]. Though rare, these cases remind us that, while TNF antagonism generally has high success rates, the introduction of foreign proteins (biologic therapy) into patients with a predisposition for autoimmunity may rarely induce unanticipated and contrary results.

While the evidence is limited to small case series and case reports, adalimumab and infliximab are superior to etanercept for controlling uveitis refractory to other immunomodulatory therapy [56, 57]. Most uveitis specialists do not recommend etanercept for the treatment of uveitis; [58] hence, a patient with active uveitis while taking etanercept for underlying bowel disease may appropriately be switched to another TNF-inhibitor with the consent of the prescribing physician.

Salicylazosulfapyridine (sulfasalazine), a prodrug composed of 5-aminosalicylic acid (5-ASA) and sulfapyridine, is a common first-line therapy for IBD. As such, ophthalmologists treating IBD-associated uveitis will likely encounter patients already under therapy with sulfasalazine. It is important to note that, despite a lack of proven efficacy as a primary therapy for uveitis, sulfasalazine significantly decreases the number of annual flares of anterior uveitis, at least in patients with ankylosing spondylitis [59, 60]. The data for IBD patients with uveitis treated with sulfasalazine are limited, but similar conclusions may be extrapolated. In a prospective study of 10 patients with three or more flares annually of acute anterior uveitis, there was one IBD patient in the cohort; sulfasalazine reduced the annual flares of uveitis in this patient from four to zero [59].