Extraintestinal manifestations of pediatric IBD patients cannot be discussed without first mentioning growth failure which is estimated to occur in 30% of children with Crohn disease and in 5–10% with ulcerative colitis [7]. Children can present with an obvious lack of growth such as a height below the 5th percentile for age, or growth changes can be more subtle with a gradual flattening of the child’s height velocity that is only evident upon plotting of multiple height measurements on a growth chart. Some children can have delays in bone maturation and pubertal development. It is important to not merely assume that growth failure is a consequence of gastrointestinal manifestations as decreases in weight and height velocities can precede any clinical evidence of bowel disease [19]. Thus, the concept of viewing growth failure as an independent manifestation of IBD will help health care providers develop a higher index of suspicion for the diagnosis of IBD in children presenting in this manner, even if they do not have gastrointestinal complaints.

IBD-associated growth failure could be secondary to deficient nutrient intake, poor digestion and absorption, as well as increased metabolic demands; however, the most likely etiology remains chronic caloric insufficiency [20]. Unfortunately, treatment for the IBD, especially with chronic corticosteroids, can have deleterious effects on overall growth and this needs to be weighed against the detrimental effects of the inflammatory process on growth. In addition to consideration of immunomodulator and biologic therapies earlier in the disease course of pediatric patients, administration of oral or enteral formula feedings should be considered to rehabilitate the growth-stunted patient. A more extensive review can be found in the chapter devoted to growth issues in pediatric IBD.

Joint inflammation is a commonly seen extraintestinal manifestation of IBD in both adults and children [7]. Arthralgias are a frequent complaint and, in fact, arthritis occurs in up to a quarter of children with IBD [21]. Similar to most other extraintestinal manifestations, symptoms of joint inflammation may occur before or after the development of bowel disease. Joint manifestations can be divided into an axial form (involvement of the axial spine and sacroiliac joints) and a peripheral form (involvement of larger joints such as the knees, ankles, hips, wrists, and elbows).

The axial form of joint involvement includes ankylosing spondylitis and sacroiliitis. Ankylosing spondylitis, which is associated with the HLA-B27 antigen, is more commonly associated with ulcerative colitis and occurs in less than 2% of IBD patients. Symptoms include back stiffness, pain, and eventually stooped posture as well as peripheral joint complaints. Almost all of these patients will have involvement in their sacroiliac joints. On the other hand, asymptomatic sacroiliitis is more common with an estimated incidence of 10–52% [6]. Sacroiliitis is often not diagnosed especially in its early stages unless sought after with bone scans or noted on computed tomography enterography [22]. Isolated sacroiliitis seems not to be associated with HLA-B27 [3]. Asymptomatic HLA-B27 negative patients with normal spinal mobility do not require specific treatment. Though ankylosing spondylitis has been shown to respond to sulfasalazine in multiple double-blind studies, none of the studies addressed ankylosing spondylitis in IBD patients [23]. In fact, therapy for IBD-related symptomatic axial disease primarily involves physical therapy and an exercise program to stop the progression of any disability and deformation.

Peripheral joint inflammation is most frequently reported with Crohn disease and is most typically associated with colonic inflammation although it can also be associated with small bowel disease [6]. The patient usually presents with erythema, swelling, and decrease range of motion in an asymmetric pauciarticular pattern. Fortunately, joint deformity is uncommon. The arthritis tends to worsen during times of increasing bowel disease and there is an association with other extraintestinal manifestations such as those of the skin, mouth, and ocular systems. In fact, patients with involvement of these systems can share serologic markers such as elevations in antibody levels against exocrine pancreas compared to other IBD and non-IBD patients [24].

Primary treatment of the bowel inflammation with 5-aminosalicylate medications, corticosteroids, or other immunomodulating agents is the first course of action for joint inflammation [7]. Often resolution is achieved with this approach in less than 8 weeks [21]. Treatment with nonsteroidal anti-inflammatory agents and cyclooxygenase-2-inhibitors has the potential for gastrointestinal mucosal injury and should be avoided if possible. In refractory cases, consideration is given to methotrexate and intraarticular corticosteroid injections. Studies have also shown that infliximab is efficacious in the treatment of spondyloarthropathies such as the articular and musculoskeletal findings in IBD [6].

There has been recent increasing interest in identifying osteopenia and osteoporosis in patients with IBD especially given that IBD commonly presents during adolescence and young adulthood when bone mass is being rapidly attained. In adult populations, the overall prevalence of osteoporosis in IBD is estimated between 4 and 40% with increasing prevalence in older patients [3]. A large population-based adult study reported an osteoporosis prevalence of 15% and relative risk of 1.4 for fractures in IBD patients compared to the general population [25]. Prevalence of osteopenia and osteoporosis in the pediatric population is estimated between 8 and 30% based on several smaller studies [9, 26]. The increased risk of eventually developing osteoporosis in IBD patients, especially those with Crohn disease, is secondary to multiple factors including inadequate intake or malabsorption of calcium and vitamin D, corticosteroid use, low estrogen states in females, and negative effects of circulating proinflammatory cytokines [27]. This osteoporosis can make the patients prone to bone fracture, bone deformities, and chronic pain.

Diagnosis of osteopenia/osteoporosis is made with dual-energy X-ray absorptiometry (DEXA) which measures bone mineral density in the spine, femoral neck, or other bones rapidly and with low amounts of radiation. Treatment with calcium and vitamin D may prevent further deterioration of bone but not necessarily help in recovery of lost bone density. Prevention has not been well studied in IBD patients but it would be prudent to ensure intake of at least the recommended daily requirement for age of calcium and vitamin D, proper exercise, and minimization of corticosteroid usage to maximize the pediatric patient’s potential in achieving an appropriate peak bone mass.

Other bone complications in IBD patients include osteonecrosis of the femoral head, hypertrophic osteoarthropathy, and chronic recurrent multifocal osteomyelitis (CRMO). Osteonecrosis of the femoral head is usually associated with patients who have received chronic steroids and have complaints of hip or knee pain. Clubbing or hypertrophic osteoarthropathy is another bone manifestation associated with IBD especially with small intestinal Crohn disease. The etiology, though unknown is postulated to involve increased blood flow to the fingers and hence increased connective tissue growth secondary to circulating cytokine production [6]. Chronic recurrent multifocal osteomyelitis (CRMO), rarely described in children with IBD, is an aseptic inflammatory bone disease that typically affects the long bones and clavicles [28].

Oral lesions can arise at anytime in patients with IBD and at any age, but it occurs more common in children and is often independent of the intestinal disease severity [29]. Recurrent aphthous lesions are the most common oral lesions associated with IBD with a reported incidence of approximately 8–14% in pediatric IBD patients with higher rates in Crohn disease compared to ulcerative colitis [9, 10, 12]. Aphthous lesions tend to parallel intestinal disease though they often can predate intestinal symptoms. Other oral lesions can consist of lip swelling, fissures, and gingivitis which can demonstrate granulomas on histology [30]. Orofacial granulomatosis is a rare syndrome with chronic swelling of the lips and lower half of the face combined with oral ulcerations and hyperplastic gingivitis that has been reported in three dozen Crohn cases [31]. Orofacial granulomatosis can be seen in other disorders such as foreign body reaction, tuberculosis, sarcoidosis, and idiopathic causes which share similar histopathologic features [29]. Another rare disorder seen in association with ulcerative colitis patients is pyostomatitis vegetans which can present with oral and cutaneous findings in the axillae, genital areas, and scalp. The oral lesions consist of multiple neutrophil and eosinophil-filled pustules on erythematous bases which can erode and fuse to form shallow ulcers that have been described as being “snail track” configuration [32]. Oral lesions in IBD patients could also be a result of nutritional deficiencies, specifically low levels of zinc, folic acid, niacin, and vitamin B-12 [29].

Treatment of oral lesions is usually reserved for those causing significant discomfort and may involve topical, intralesional or systemic corticosteroids, dapsone, or preparations directed at the bowel disease including immunomodulators, antitumor necrosis factor alpha (anti-TNFα) agents, and thalidomide [29, 33].

Cutaneous manifestations of IBD can be classified into three principal groups: granulomatous, reactive, and secondary to nutritional deficiency. Granulomatous skin manifestations have the same histological features as the bowel disease and can include perianal and peristomal ulcers and fistulas, oral granulomatous ulcers, and metastatic Crohn disease. The latter is a rare complication that manifests as subcutaneous nodules or ulcers mainly in the lower extremities and on occasion can occur in the genital areas. It appears unrelated to bowel activity and can be treated successfully with corticosteroids, antibiotics, azathioprine, methotrexate, and infliximab [6].

Of all the skin manifestations associated with IBD, erythema nodosum and pyoderma gangrenosum (Fig. 10.1) are the most common; however, in the pediatric patient, erythema nodosum, which is more commonly associated with Crohn disease than with ulcerative colitis, is encountered more frequently [7, 9]. Erythema nodosum presents as tender, subcutaneous, erythematous nodules, usually on the extremities, especially the lower legs and the majority of patients with this skin manifestation will have associated joint pain or develop arthritis. Children may appear systemically ill with fever. Over days to weeks, the nodules will flatten, turn brown or gray, and can be mistaken for bruises. Histologically, erythema nodosum is as a septal panniculitis consisting of a lymphohistiocytic infiltrate. The prevalence in all IBD patients, adult and pediatric, is estimated between 3 and 15% [25]. Exacerbations of erythema nodosum correlate most often with increased intestinal inflammation, hence treatment towards the bowels is considered a primary form of management. Recent reports in children have shown good response to infliximab [34].

Pyoderma gangrenosum is an ulcerating lesion often correlating with exacerbations of the bowel disease; however, it can persist for long periods while the intestinal inflammation is clinically quiescent. Fortunately it is relatively rarely associated with IBD with a reported incidence of 2% in UC patients and a smaller number in Crohn patients [34]. The lesions are often painful and located on the lower extremities. Histopathology reveals endothelial injury with fibrinoid necrosis of blood vessels and marked neutrophilic and lymphocytic infiltrates. Treatment is difficult and patients may require large doses of systemic corticosteroids or immunomodulators as well as topical ulcer care. Infliximab has shown to be effective in refractory cases; however some extreme cases might require grafting [6, 34].

Sweet’s syndrome is another very rare reactive cutaneous disorder associated with IBD. It is a neutrophilic dermatosis presenting with painful erythematous plaques or nodules often associated with fever and leukocytosis. Usually there is good response to corticosteroids and a recent study demonstrated benefit of cyclophosphamide in steroid refractory patients [35].

Nutritional issues, such as trace mineral and vitamin deficiencies, can be common in children with IBD, especially Crohn disease; however skin disorders secondary to these are unusual. There are rare reported cases of acrodermatitis enteropathica, pellagra, and scurvy secondary to zinc, niacin, and vitamin C deficiency, respectively.

Vulvar lesions have also been associated with IBD with patients presenting with vulvar ulcers, labial swelling, exophytic lesions, condylomatous lesions, and abnormalities on pap smear. Most often the histopathology demonstrates noncaseating vulvar granulomas but dysplasia and carcinoma have also been reported [36].

The most common eye manifestations of IBD are episcleritis and uveitis [7]. These are often associated with other extraintestinal manifestations, especially arthritis and erythema nodosum. Episcleritis (Fig. 10.2), inflammation of the blood-rich episclera, tends to parallel bowel activity and is often confused with conjunctivitis as the patients present with eye redness and burning. Episcleritis does not impair vision and usually responds clinically to topical corticosteroids. If visual impairment is present, the possibility of scleritis, which can occur with protracted intestinal disease, needs to be considered and an emergent evaluation by an ophthalmologist is required to evaluate for retinal detachment or optic nerve swelling.