Comorbidities

Introduction

Both ulcerative colitis (UC) and Crohn’s disease (CD) have the potential for systemic involvement, with disease manifestations extending beyond the gastrointestinal tract. Extraintestinal symptoms may appear prior to the diagnosis of inflammatory bowel disease (IBD), simultaneously with intestinal symptoms, or even following surgical removal of affected bowel segments. Among the extraintestinal conditions that can be considered as part of the clinical spectrum of intestinal disease, there are two primary groups: extraintestinal manifestations (EIMs), defined as immune-mediated conditions that are linked physiopathologically to the primary condition itself, and extraintestinal complications, or non–immune-mediated conditions that are secondary to bowel disease (Table 6-1). Extraintestinal complications can be subdivided into those resulting from the long-term anatomical and physiological consequences of the disease itself (e.g., micronutrient deficiencies resulting from loss of function of diseased or resected bowel segments) and those due to treatments for the primary condition (e.g., drug-induced nephrotoxicity, fatty liver disease, peripheral neuropathies).

This section focuses on the EIMs most commonly experienced by IBD patients, including arthritis, axial arthropathy/ankylosing spondylitis, aphthous stomatitis and others. EIMs can affect nearly every organ, but most commonly affect the joints, skin and eyes. Many EIMs follow the course of intestinal disease activity (e.g., peripheral arthritis and erythema nodosum) and tend to improve with successful treatment of the underlying bowel disease, whereas others are activity-independent (e.g., primary sclerosing cholangitis [PSC] and ankylosing spondylitis). Given that EIMs are often associated with reduced quality of life, possibly more than the intestinal disease itself, clinicians should be aware of their presentation to facilitate their rapid diagnosis and treatment.

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Epidemiology of EIMs in UC and CD

The reported frequency of EIMs in patients with IBD varies from 6% to up to 47%. The wide range of reported frequencies is likely due in part to methodological differences between studies, including differences in length of follow-up, definitions of manifestations and importantly, the selection of patient cohorts. Many published studies rely of patients from referral centers, and thus report high EIM prevalence rates. In contrast, population-based studies are more likely representative of the IBD population and in general report low-to-moderate prevalence rates. For example, a 2015 European population-based cohort study reported a more conservative overall EIM prevalence rate of 17.6%.

The Swiss IBD Cohort Study (SIBDCS) has been including patients with IBD from Switzerland since 2006. A 2011 publication of the SIBDCS aimed to determine the frequency of EIMs in UC and CD and to identify risk factors, if any, associated with specific EIMs. Of the enrolled patients, 61% had CD and 39% had UC. At least one EIM occurred in 31% of UC patients.

A 2015 analysis of SIBDCS aimed to assess the cumulative risk of developing one or several EIMs relative to the time of diagnosis. In total, 1249 patients were included, of which 58.8% had CD, 38.7% had UC and 2.5% had indeterminant colitis (IC). Of these patients, 33.7% with CD, 21.7% with UC and 13% with IC suffered from at least one EIM before or after diagnosis with IBD. The most common EIMs in all patients with IBD were peripheral arthritis (70.0%), followed by aphthous stomatitis (21.6%) and axial arthropathy/ankylosing spondylitis (16.4%). Notably, in a quarter of patients, EIMs were diagnosed prior to the diagnosis of IBD.

Pathogenesis

Many patients with CD or UC suffering from EIMs have extensive colitis, suggesting an association between EIMs and inflammatory processes. Additionally, the development of one EIM has been reported to increase a patient’s susceptibility to developing other EIMs, particularly among a group of EIMs consisting of peripheral arthritis, erythema nodosum and involvement of the biliary tract and the eye. High levels of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA), especially in UC patients, have been associated with PSC, erythema nodosum and uveitis, supporting an autoimmune mechanism. Additionally, memory T cells, which are circulating mucosal leukocytes, are known to infiltrate effector tissues and organs to induce inflammation beyond the gut epithelium.

Genetic factors also play a role in developing extra­intestinal manifestations. Implicated genetic markers associated with the susceptibility to develop EIMs include several human leukocyte antigen (HLA) variations. For example, HLA-B8/DR3 is associated with a high risk for PSC in UC patients, whereas HLA-DRB1*0103, HLA-B*27 and HLA-B*58 are associated with EIMs of the joints, skin and eyes, respectively, in all patients with IBD.

EIMs in Pediatric Patients

Rates of EIMs are higher in pediatric IBD patients compared to adults, with up to 28% presenting with an EIM at diagnosis. In those pediatric IBD patients without an EIM at diagnosis, at least one will develop within 15 years in 29% of patients. The most common EIMs that present in children are arthritis (8% to 26%) and aphthous stomatitis (7% to 21%). Similar to adults, PSC is more common in pediatric UC patients than in pediatric CD patients, being three times more likely to develop the condition. Since EIMs may develop before intestinal symptoms in up to 35% of children, IBD should be suspected in children presenting with EIMs to prevent a delay in diagnosis and treatment of IBD.

Selected Comorbidities

In the following section, some of the most common EIMs experienced by IBD patients will be discussed. Extraintestinal manifestations and complications of IBD as well as treatment options are summarized in Table 6-1.

Joint Manifestations

Manifestations in the joints are the most common EIM of IBD, occurring in between 20% and 30% of patients. Joint involvement can be classified as peripheral or axial arthropathy, with peripheral arthropathies being more common among female patients and in patients with colonic disease. Isolated sacroiliitis, inflammatory back pain and ankylosing spondylitis (AS) make up the axial arthropathies, with CD patients (5% to 22%) being affected more frequently than UC patients (2% to 6%). Axial arthropathies are estimated to be 20-fold more frequent in IBD patients than in the general population. The most common symptoms include back pain and morning stiffness.

Axial arthropathies do not typically follow the course of the underlying IBD and axial joint involvement commonly precedes the first intestinal symptoms. A strong link is especially present between AS and IBD: 6.5% of patients with AS develop IBD, and the prevalence of AS in patients with IBD is up to 10%. Even in patients with AS and without clinical symptoms of IBD, up to 70% present with microscopic gut inflammation at colonoscopy. This relationship has a strong genetic link: in patients with IBD and concomitant AS, 25% to 78% are HLA*B27 positive.

Mucocutaneous Manifestations

Mucocutaneous manifestations occur in 9% to 19% of CD patients and 9% to 23% of UC patients. The most common mucocutaneous manifestations in IBD patients are erythema nodosum (10% to 15% in CD; 3% to 10% in UC), pyoderma gangrenosum (0.1% to 1.2% in CD; 1% to 5% in UC) and aphthous stomatitis (5% to 10% of IBD patients). Erythema nodosum and aphthous stomatitis typically parallel disease activity, whereas pyoderma gangrenosum may be independent. Other skin manifestations may include psoriasis, vasculitis and Sweet’s syndrome.

Erythema nodosum, the most common skin manifestation in IBD patients, parallels disease activity, more commonly affects females and patients with CD and is associated with ocular and joint manifestations. It presents as painful and tender red nodules 1 cm to 5 cm in diameter (Figure 6-1), typically located bilaterally on the ventral lower legs but can also involve the truck, arms, face and neck. Erythema nodosum is often self-limiting and treatment for the underlying gastrointestinal disease often improves lesions, although steroids or other therapies may be recommended in some individuals with persistent, painful lesions. Relief can also be achieved through leg elevation, use of compression stockings and analgesics. If the condition does not improve with treatment and improvement of the underlying bowel disease, then alternative causes should be considered.

Pyoderma gangrenosum is one of the few EIMs that occurs more frequently in patients with UC than CD. Although it is reported in only 1% to 2% of IBD patients overall, up to 50% of patients with pyoderma gangrenosum have IBD. It is a severe condition that first presents as a single papula that rapidly enlarges into deep painful ulcers with a central necrosis surrounded by purplish, indistinct borders (Figure 6-2). Pyoderma gangrenosum typically occurs on the lower limbs but can affect any cutaneous region or be parastomal. Its location will frequency occur at sites of previous minor trauma, such as from biopsy or venous puncture, reflecting pathergy phenomenon (altered skin reactivity to minor trauma). If pathergy phenomenon is suspected, then diagnosis should be made clinically, if possible, to avoid development of additional lesions. The course of pyoderma gangrenosum does not typically parallel gut activity. Dermatology consultation may be necessary. Treatment options may include local or systemic steroids, immune modulatory therapy or biologic agents.

Aphthous stomatitis affects up to 10% of IBD patients, with painful lesions typically located on the buccal and labial mucosa, tongue and oropharynx (Figure 6-3). Aphthous stomatitis parallels underlying intestinal disease activity and responds to disease-specific treatment. Antiseptic mouthwashes and topical corticosteroids may also temporarily improve symptoms.

Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, is a skin disease characterized by a sudden onset of fever, elevated white blood cell count and well-demarcated papules and plaques showing dense infiltrates by neutrophil granulocytes. Sweet’s syndrome is considered a cutaneous marker of systemic disease, such as malignancy or inflammatory disease, primarily during an exacerbation of the underlying disease. The lesions usually respond to topical or oral corticosteroids.

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Ocular Manifestations

Ocular EIMs occur in 2% to 6% in IBD patients, the most common including mild conjunctivitis and episcleritis, with more severe inflammation including scleritis and anterior uveitis (Figure 6-4). Ocular EIMs may develop shortly after disease onset, often occur together with joint and/or cutaneous manifestations and recur in approximately 30% of patients. Episcleritis typically parallels intestinal disease activity and symptoms include burning and acute hyperemia. Scleritis should be considered if deeper layers of the eye are involved. Inflammation in both episcleritis and scleritis often responds to IBD-specific treatment, such as immunosuppressants or systemic corticosteroids. Symptoms of uveitis include eye pain, blurred vision, photophobia and headaches. Prompt and aggressive treatment of uveitis is required to prevent permanent damage or vision loss and often includes topical or systemic corticosteroids. Since the consequences of ocular manifestations can be serious, early referral to an ophthalmologist is recommended.

Primary Sclerosing Cholangitis (PSC)

PSC is a chronic cholestatic disease characterized by progressive inflammation of the intrahepatic and extrahepatic bile ducts (Figure 6-5A), followed by fibrosis, possibly leading to biliary cirrhosis with liver failure. It is estimated to affect 1% to 2% of CD patients and 2% to 4% of UC patients. When including small-duct PSC, the estimated overall prevalence ranges between 2.4% and 11% and is more common in males. Approximately 80% of patients with PSC will have concomitant IBD. Due to the strong associated between IBD and PSC, patients presenting with PSC should undergo evaluation for IBD.

Symptoms of PSC include fatigue, weight loss, abdominal pain, pruritus and intermittent jaundice. PSC is diagnosed based on:

• Elevated liver function tests: typically increases in alkaline phosphatase and bilirubin
• Serology: positivity for autoantibodies in 65% to 88% of patients, including positivity for anti-nuclear, anti–smooth-muscle, and anti-perinuclear cytoplasmic antibodies
• Magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP): irregular bile ducts with multifocal strictures are characteristic of the condition (Figure 6-5B-C)
• Histological findings, including a periductal fibrosis “onion skin” pattern (Figure 6-5D).

Small-duct PSC should be considered in patients with normal features on MRCP, since its typical features only show in liver biopsy samples.

PSC is an independent risk factor for the development of cholangiocarcinoma and colorectal cancer and is therefore considered a precancerous condition. As such, annual surveillance colonoscopy is recommended in affected patients and should be initiated at the time of PSC diagnosis. These patients may also additionally be considered for chromoendoscopy at the time of their annual surveillance colonoscopy examinations. No medical therapies have been shown to prevent progression of PSC, although 10 to 15 mg/kg/day ursodeoxycholic acid may be considered in some patients. Orthotopic liver transplantation is the therapy of choice for progressive disease, with a favorable 5-year survival rate of 80%, except in patients with cholangiocarcinoma.

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Anemia

Anemia is another common extraintestinal manifestation in patients with IBD, with an estimated prevalence of between 19% and 32%. It can be caused by a variety of mechanisms, including chronic disease, chronic blood loss, malabsorption, inadequate dietary intake, drug toxicity and others. Iron deficiency is the main cause of anemia in IBD patients and can be treated through oral or IV supplementation, with rapid improvement in most patients. In patients not responding to IV supplementation, alternative causes should be considered. Macrocytic megaloblastic anemia can be caused by vitamin B₁₂ and folate deficiency; this form of anemia is more common in CD patients since these nutrients are absorbed by the ileum.

Low Bone Mineral Density and Osteoporosis

Low bone mineral density is a common but often overlooked complication in IBD patients. The estimated overall prevalence of low bone mass in IBD patients ranges from 18% to 42%, with the overall prevalence of patients with IBD developing osteoporosis estimated to be 15%. Fracture risk is increased in IBD patients by approximately 40% compared to the general population. Risk factors for abnormal bone mineral density (BMD) include elevated inflammation and hypogonadism induced by IBD, malabsorption of calcium and vitamin D, advanced age, low physical activity, smoking and systemic corticosteroid use. Screening by dual-energy X-ray absorptiometry (DEXA) is recommended for select groups of patients, including:

• Post-menopausal females
• Male patients >50 years of age
• Patients with chronic corticosteroid use (therapy ≥3 months)
• Patients with a history of vertebral fractures
• Patients with hypogonadism.

Taking steps to prevent bone loss in patients can be achieved by minimizing use of systemic corticosteroids, use of steroid-sparing agents in corticosteroid-dependent patients and appropriate treatment of osteoporosis in affected patients. Regular supplementation with vitamin D (800 IU to 1,000 IU per day) and calcium (1,200 mg per day) is recommended in patients treated with systemic corticosteroids. In IBD patients with diagnosed osteoporosis, treatment recommendations for osteoporosis do not differ from those for the general population, with treatments shown to prevent further bone loss including bisphosphonate therapy, calcitonin and testosterone replacement in men with hypogonadism. Recent guidelines have been published which recommend that patients with conventional risk factors for abnormal BMD with UC and CD should undergo screening for osteoporosis with BMD testing at the time of diagnosis and periodically hereafter.

Conclusion

Overall, EIMs are common features of IBD affecting nearly every organ system, with certain EIMs having the potential to be more debilitating than the intestinal symptoms themselves. As such, early recognition and treatment are critical to patient care. Many EIMs parallel intestinal disease activity and can be sufficiently relieved through treatment of the underlying IBD. However, in those EIMs that are activity-independent, interdisciplinary management is generally required. In addition to EIMs, extraintestinal complications brought about by therapies used to treat IBD or long-term consequences of the disease itself, such as osteoporosis and anemia, can seriously impact patient quality of life and should be assessed for regularly as a preventative measure.