OVER THE LAST 2 DECADES, the treatment and management of inflammatory bowel disease (IBD) has changed drastically.

New biologic agents have altered the course and prognosis of IBD, allowing many patients to have an increased quality of life. While many specialty pharmacists have a good grasp of the treatment and management of intestinal manifestations of IBD, the understanding of extraintestinal manifestations (EIM) is often less clear. The prevalence of patients with at least 1 EIM has been found to be as high as 40%, with over 25% having more than 1 EIM.1

Therefore, without a basic understanding of how EIMs play into the treatment and prognosis of IBD, specialty pharmacists may be missing important clinical data needed to fully assess the efficacy and appropriateness of drug therapy. The focus of this article will be to highlight common EIM that affects patients and to determine how we, as specialty pharmacists, can take a more active role in the management of this complex disease state. IBD is a systemic inflammatory condition, with bowel symptoms being the most prevalent manifestation.2

Pro-inflammatory cytokines do not restrict themselves to the bowel. This is why we see so many IBD patients with EIM. Almost any organ system can be affected by EIM. The most common systems affected are the dermatologic, ocular, hematologic, and musculoskeletal systems.2

Disease state activity often mirrors the likelihood of having an EIM, with more active disease having increased complications and a higher prevalence of EIM.1 Some patients experience EIM prior to their diagnosis of IBD. Patients being treated for arthritis or ankylosing spondylitis may, in fact, have IBD. While many patients with EIM will respond to medications that treat intestinal symptoms, appropriate drug therapy and early detection and treatment of EIM are extremely important in the management of IBD.

Arthritis
Musculoskeletal manifestations, often in the form of arthritis, impact the largest number of IBD patients.3 The 2 main types of arthritis seen in IBD patients are peripheral and axial arthropathies. The Oxford Group breaks down peripheral arthropathies into 2 distinct groups, pauciarticular and polyarticular arthritis.3 The 2 peripheral arthropathies differ in the number of joints affected, type of joint affected, length of recovery, and if flares occur independently of intestinal activity.

Pauciarticular arthritis impacts mostly the larger weight bearing joints, affects less than 5 joints, and resolves within a few months. Polyarticular arthritis impacts mainly small joints, affects greater than 5 joints, and can persist for months to years. Worsening of pauciarticular arthritis often occurs concurrently with bowel manifestations, whereas polyarticular arthritis is largely seen as independent of disease activity.3

Axial arthropathies, including sacrolitis and ankylosing spondylitis, are also prevalent in the IBD population. Many patients with IBD have asymptomatic sacrolitis that often goes undetected until radiographic imaging is done.1 The symptoms of axial arthropathies include lower back pain, pelvic pain, and decreased spinal mobility.2

Treating the underlying bowel disease will commonly improve arthritis symptoms, although additional medications and treatments may be necessary. Disease that occurs independently of bowel disease, or that does not respond to standard care, can be treated with anti-inflammatory and disease modifying agents.3

Osteoporosis
While arthritis can readily be detected by patients, osteoporosis can occur without patients having any knowledge of it. There is a 40% greater risk of fractures in IBD patients than the general population.1 The risk of decreased bone mineral density may actually be much higher in this population than initially found. Osteoporosis is often asymptomatic until diagnosis or fracture, which makes it difficult to quantify the number of IBD patients who have osteopenia and osteoporosis. A number of factors lead to the increased risk of fractures.4

Vitamin malabsorption, prolonged steroid use, increased bone resorption due to inflammatory factors, and decreased physical activity in this population all contribute to a higher risk of osteoporosis.2 Once osteoporosis is diagnosed, it is treated in the same way as a non-IBD patient.

The standard of care for these patients is a regimen consisting of a bisphosphonate, calcium and vitamin D.2 According to the American Gastroenterological Society, IBD patients at high risk of developing osteoporosis, should be screened. High risk is classified as long-term steroid use (>3 months), postmenopausal females, males older than 50 years, hypogonadism and past fractures.1

Patients with a recent fracture or a history of fractures, should be questioned about past osteoporosis screening. In addition, patients should be counseled about how to reduce the risk of falls. There is debate as to whether early calcium and vitamin D supplementation can help reduce the risk of osteoporosis in the IBD population.

While calcium and vitamin D are recommended in this population, the underlying cause of IBD should be addressed. Therefore, appropriate drug therapy appears to be the best way to reduce the risk of developing osteoporosis for patients with IBD.

Ocular Manifestations
Osteoporosis is generally not considered to be a condition that requires immediate treatment. Diseases of the eye, on the other hand, are likely to require immediate attention. Uveitis and episcleritis occur in up to 5% of all IBD patients. These ocular manifestations often occur when other EIM are present.

Episcleritis, the inflammation of the tissue that lies between the conjunctiva and the sclera, is commonly seen in IBD patients. With episcleritis, vision is not affected and there is no sensitivity to light.5

Episcleritis is generally self-limiting, often does not require treatment, and will resolve within 7 to 10 days. Cool compresses and artificial tears can be used for eye discomfort.5 For resistant cases, topical steroids can be used. Uveitis is another condition with ocular symptoms.

Uveitis is an inflammation of the uvea and is considered an ocular emergency. Symptoms of uveitis are redness, irritation, blurred vision, photophobia, and pain.1 Uveitis must be treated quickly with steroids to control the inflammation. Treating the underlying intestinal disease will help reduce the risk of developing ocular EIM, but it is important to question IBD patients about any changes in their vision or eye health during consultations.5

Anytime an IBD patient complains of vision changes or any other eye problems, they should be referred to their provider.

Anemia
One of the most common abnormalities found during routine labs in the IBD population is anemia. Iron deficiency anemia and chronic anemia are the 2 most common types of anemia in the IBD population.6 In a recent systematic review, 68% of hospitalized IBD patients presented with anemia.6 Iron deficiency is responsible for the majority of anemia cases in this population.

There are multiple causes of iron deficient anemia. Malabsorption, decreased oral iron intake, and intestinal bleeding can all cause this form of anemia. The other common anemia seen in this population is chronic anemia. This type of anemia is due to an elevation in inflammatory cytokines.7 It is important for a clinician to determine the cause of anemia to appropriately treat the underlying cause.

Often, oral or intravenous administration of iron and treatment of the underlying intestinal disease can improve the anemia. It is important to note that, although oral iron is commonly the first line of therapy, it is often poorly tolerated.7 Many patients on oral iron have gastrointestinal issues, which may worsen bowel symptoms in IBD patients with poor disease control.6

Patients on iron therapy should be counseled on how to decrease the risk of gastrointestinal side effects. Occasionally, erythropoietin or other erythropoiesis-stimulating agents must be administered to bring up the hematocrit and hemoglobin.6

Patients who complain of fatigue should be questioned about the severity, start date of the symptoms, and history of anemia. Patients with poorly controlled intestinal disease are expected to have more fatigue and an increased likelihood of developing anemia. Patients suspected of having anemia should be referred to their provider.

Dermatologic Manifestations
Dermatologic manifestations can also present as EIM. Two of the more common dermatologic manifestations are erythema nodosum (EN) and pyoderma gangrenosum (PG).1 EN is an inflammation of the subcutaneous tissue. It presents as tender, red, palpable lumps and is commonly found on the shins. EN doesn’t usually require additional medications for treatment and generally resolves in 4 to 5 weeks.

Supportive therapy with compression stockings, rest, and leg elevation will help expedite the resolution.8 In addition, IBD patients are more likely to have EN during an intestinal flare-up of IBD.1 Pyoderma gangrenosum is a condition in which a necrotic ulcer forms on the patient’s skin. This usually occurs after minor trauma to the affected area.

There are currently no standardized treatment guidelines for the management of PG.8 Cleaning the ulcer and proper wound care, combined with treatment of the underlying intestinal disease, will help with treatment.8 Occasionally, steroids are required to treat the necrotic ulcers.

Both EN and PG occur more frequently during IBD flares, and in patients with more active intestinal disease.8 Patients should be questioned on the start date of symptoms, if they have ever had any type of dermatologic manifestation of IBD, and how often they have bowel flare-ups. Providers should be notified of these skin manifestations.

Role of Specialty Pharmacists
In evaluating patients with IBD, a complete understanding of this disease state is necessary. Asking questions related only to bowel symptoms and flare-ups give us just a portion of the picture. While it is still important to ask about flare-ups in regards to intestinal symptoms, we should also be asking our patients about EIM.

We need to be able to differentiate between EIM and other unrelated conditions. Patients complaining of arthritis, a history of fractures, skin issues, eye symptoms, or any other recently changed disease state should be questioned to determine if their underlying IBD may be the cause.

If a patient is having issues with EIM, it may be an indication that their therapy is not effectively controlling their IBD. Patients having a difficult time controlling their IBD may need to be referred to their provider to discuss an alternative medication. Even if a patient has had success with a certain medication in the past, over time this medication may lose efficacy in managing the patient’s symptoms. If this is the case, it is important that we emphasize to the patient the importance of discussing alternative treatment options with their provider.

Pharmacists are trained to focus on medication-related side effects and signs of whether the medication is having the desired efficacy. As specialty pharmacists, we are able to utilize our training and ask appropriate questions to determine patient responses to therapy, as well as assess their disease state management.

A good specialty pharmacist possesses the skills and training to ask the right questions. Appropriate and relevant questions help determine the appropriateness of the medication.

Additionally, a good pharmacist knows when a patient needs to be referred to their provider for an additional consultation. Educating ourselves about EIM and taking a more active role in patient care translates into better outcomes by decreasing the number of patients with inadequately controlled IBD. 

References
  1. Levine JS, Burakoff R. Extraintestinal Manifestations of Inflammatory Bowel Disease. Gastroenterology & Hepatology. 2011;7(4):235-241.
  2. Ardizzone S, Puttini PS, Cassinotti A, Porro GB. Extraintestinal manifestations of inflammatory bowel disease. Dig Liver Dis. 2008;40 Suppl 2:S253–9.
  3. Signe Larsen , Klaus Bendtzen , Ole Haagen Nielsen. Extraintestinal manifestations of inflammatory bowel disease: Epidemiology, diagnosis, and management. Annals of Medicine Vol. 42, Iss. 2, 2010.
  4. Lima CA, Lyra AC, Rocha R, Santana G. Risk Factors for Osteoporosis in Inflammatory Bowel Disease Patients. World Journal of Gastrointestinal Pathophysiology.2015;6(4):210-218.
  5. Mady R, Grover W, Butrus S. Ocular Complications of Inflammatory Bowel Disease. Scientific World Journal. 2015.  http://dx.doi.org/10.1155/2015/438402.
  6. Stein J, Dignass A. management of iron deficiency anemia in inflammatory Bowel Disease- A Practical Approach. Annals of Gastroenterology. 2013;26(2):104-113.
  7. Murawska N, Fabisiak A, Fichna J. Anemia of Chronic Disease and Iron Deficiency Anemia in Inflammatory Bowel Diseases: Pathophysiology, Diagnosis, and Treatment. Inflammatory Bowel Disease. 2015;0:1-11.
  8. Pellicer Z, Santiago JM, Rodriguez A, Alonso V, Anton R, and Bosca MM. Management of cutaneous disorders related to inflammatory bowel disease. Annals of Gastroenterology. 2012;25(1):21-26.
About the Author
ADAM FURMAN, PHARMD received his Doctor of Pharmacy degree from Oregon State University in 2012.  Dr. Furman joined Ardon Health as a clinical pharmacist in December 2014 and was promoted to Clinical Pharmacist Lead in 2015.  In this position, he has taken an active role in care management, development of clinical programs, and inventory management. Dr. Furman serves as a member of the Clinical Oversight Body at Ardon Health, preparing and presenting clinical programs and quality improvement measures. Prior to joining Ardon Health, Dr. Furman spent 2 years working as a pharmacist in a community and long term care setting