Stopping, continuing, or restarting immunomodulators and biologics when an infection or malignancy develops.

REVIEW ARTICLE

Stopping, Continuing, or Restarting Immunomodulators and Biologics When an Infection or Malignancy Develops Jason M. Swoger, MD, MPH and Miguel Regueiro, MD

Abstract: Thiopurines and biologics are being used earlier and more frequently for the treatment of Crohn’s disease and ulcerative colitis. These medications are generally well tolerated and usually do not require cessation due to a side effect. Rare but serious infections and cancers may develop in patients on these immunosuppressants. Evidence-based data are lacking to guide physicians on whether continuing or stopping thiopurines and biologics is necessary and, when a side effect does occur, if and when restarting these medications is feasible. The aim of this review was to outline the infectious and malignant complications that may develop on these treatments and to provide recommendations for continuing, stopping, and restarting thiopurines and biologics once a patient develops a treatment-related complication. These are not formal guidelines and should not replace individualized care by the treating physician. (Inflamm Bowel Dis 2014;20:926–935) Key Words: biologic therapies, complications of IBD, immunomodulators, infectious agents in IBD, lymphoma in IBD, side effects of medications

T

he inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) are chronic diseases requiring longterm maintenance medications. The majority of patients with IBD will require thiopurine (azathioprine [AZA] or 6-mercaptopurine [6MP]) and/or biologic therapy during their disease course. These medications have been associated with several side effects, and patients may have to interrupt or discontinue therapy due to these treatment-related complications. It should be noted that corticosteroids remain among the most toxic of IBD medications with more than 50% of patients developing side effects that require discontinuation.1,2 Approximately 20% of patients taking AZA/6MP discontinue the medication due to a side effect.3,4 Allergic reactions and nausea are the most common side effects, but 5% of patients can have serious infections and less than 0.1% develop treatmentrelated lymphoma.2,4–6 Approximately 10% of patients treated with an anti–tumor necrosis factor (anti-TNF) agent stop therapy due to side effects.2 Allergic reactions are most common (3%–20%), with serious infections (3%) and lymphoma (,0.1%) occurring less frequently.1,7–9 Age, gender, geographical location, and the type of medication have been linked to certain adverse events. Specifically, the thiopurines are associated with viral infections, especially Received for publication December 11, 2013; Accepted January 19, 2014. From the Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. M. Regueiro has served as a consultant for Abbvie, Janssen, Takeda, UCB, and Shire; J. M. Swoger has served as a consultant for TNI BioTech. Reprints: Miguel Regueiro, MD, Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, 200 Lothrop Street, PUH-C Wing Mezzanine Level, Pittsburgh, PA 15213 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000002 Published online 19 March 2014.

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in young males, and anti-TNFs with bacterial and fungal infections, predominantly in older patients.4,5,9–11 Male patients are at higher risk for developing lymphoma from thiopurines, while older age and longer duration of thiopurine therapy are associated with nonmelanoma skin cancers and lymphoma.6,12,13 Stopping the medication will improve most infections and may reverse Epstein–Barr virus (EBV)–associated lymphomas (thiopurines).14 Conversely, the nonmelanoma skin cancers and hepatosplenic T-cell lymphomas do not seem to regress with cessation of AZA/6MP. Taking into account the gender, age, and geographical associations when prescribing immunosuppressive class medications, will allow the treating physician to better tailor IBD treatment. There are numerous publications outlining IBD treatment– related side effects but limited data or guidelines on how to manage patients who develop these events. This report is based on a lecture M. Regueiro, MD, delivered at the Advances in Inflammatory Bowel Disease course in 2012 in Hollywood, FL, entitled: “To Stop or Not To Stop Immunomodulators and Biologics When an Adverse Event Occurs? That is the Question.” This article summarizes certain adverse events related to thiopurine analogs and anti-TNFs and provides the reader with our strategy in managing these patients. We will focus our review on 2 categories of adverse events, infection and malignancy. Due to a paucity of evidence-based data on this subject, our recommendations are not formal guidelines and should not be implemented as such. Each patient who develops a medication-related side effect should receive individualized care by their treating physician.

INFECTIOUS COMPLICATIONS Infections are one of the most common reasons that patients discontinue IBD treatment. Newly diagnosed patients with IBD Inflamm Bowel Dis Volume 20, Number 5, May 2014

Inflamm Bowel Dis Volume 20, Number 5, May 2014

Stopping, Continuing, or Restarting Immunomodulators

should confirm that they are up-to-date on age-appropriate vaccinations. Vaccinations for hepatitis B, influenza, pneumococcal pneumonia, varicella, and human papilloma virus (HPV) may prevent future infection in patients who ultimately receive immunosuppressive therapy.15–17 Any medication that suppresses the immune response will predispose the patient to infection. However, the thiopurines seem to be most linked to viral infections; bacterial and fungal infections are more common with antiTNF agents.1,10,12,18–20 The magnitude of increased risk of infections caused by immunosuppression in patients with IBD is not known, but there have been several studies that have attempted to estimate this risk.1,5,9,10,21–27 A systemic review of patients with IBD receiving infliximab reported the risk of mortality from sepsis to be a rare event (4/1000 patient-years).28 The most recent report from the Crohn’s Therapy, Resource, Evaluation and Assessment Tool registry reported an increased risk of serious infection with anti-TNF therapy (odds ratio ¼ 1.43, 95% confidence interval ¼ 1.11–1.84).1 Similarly, a large meta-analysis showed an increased risk of opportunistic infections (odds ratio ¼ 2.05, 95% confidence interval ¼ 1.10–3.85), although the number needed to harm was 50.0.29 The most common serious infections in most studies were due to candida esophagitis, herpes zoster, and herpes simplex virus and had a mild clinical course with no long-term sequelae.10,23 However, several studies have not confirmed an increased risk of serious infections with antiTNF therapy.21,23,24,26,27 Considering the results from multiple studies, patients with comorbidities, older patients, those on concomitant corticosteroids or narcotics, and those with longstanding disease seem to be at highest risk of developing a treatment-related serious infection.1,9,10,24,28

Bacterial Infections There is an increased risk of bacterial infections in patients receiving immunosuppressive therapy, which seems more common with anti-TNFs than thiopurines (Table 1). The most common bacterial infections in patients with IBD are those that would

typically infect immunocompetent people, for example, streptococcal pharyngitis or Escherichia coli urinary tract infections.9 These infections are usually mild, respond to antibiotics, and do not require cessation of the IBD medications. Pneumococcal pneumonia remains the most significant bacterial infection in older patients and is especially severe in the setting of anti-TNF treatment.30 Patients who develop pneumococcal pneumonia should stop the immunosuppression and treat the infection. We will not restart immunosuppression in patients who require a prolonged hospitalization or intensive care unit management. We will cautiously restart immunosuppression after resolution of infection in patients with aggressive IBD and less severe infection. All adult patients with IBD should be vaccinated for pneumococcal pneumonia every 5 years. Opportunistic bacteria, specifically Mycobacterium species, are rare in patients with IBD but have been associated with antiTNFs, especially in older patients, and in patients residing in regions endemic for tuberculosis.10,24,29,31 Patients with latent Mycobacterium tuberculosis identified before anti-TNF treatment should receive isoniazid for 6 to 9 months.11,32,33 Anti-TNF therapy may be initiated after 2 to 4 weeks of isoniazid, as long as there are no signs or symptoms of active tuberculosis.32,34 Patients with active tuberculosis that develops in the setting of anti-TNF treatment should stop all immunosuppression and be treated appropriately.11,34 Given the drug resistant nature of tuberculosis in different parts of the world, we recommend consulting with an infectious disease specialist regarding appropriate antimycobacterial treatment. The same approach to treatment would be recommended for other opportunistic bacterial species that develop in the setting of anti-TNF treatment. Restarting the anti-TNF once the active infection has resolved depends on the severity of IBD.34 Patients in a prolonged, deep remission when the infection developed may be monitored for IBD recurrence and not restart anti-TNF therapy. It has been our experience that these patients often maintain remission without immunosuppression, but if they do recur, are responsive to re-initiation with the same anti-TNF.

TABLE 1. Continue, Stop, or Restart Medications for Bacterial Infections Bacterial Mild

Bacterial Severe

Bacterial Opportunistic

AZA/6MP

Examples: Escherichia coli UTI—streptococcal pharyngitis Note: Usually antibiotic responsive Continue

Example: Pneumococcal pneumonia Note: Every 5 yr pneumovax in adult patients with IBD Stop, but may restart once treated

Anti-TNFs

Continue

Stop, but may restart once treated

Example: Mycobacterium Note: Latent TB—INH Active TB—3 drugs Latent: do not start until 2 to 4 wk INH Active: stop, may restart after 1-mo treatment Latent: do not start until 2 to 4 wk INH Active: stop, only restart after full treatment, and if IBD is severe

INH, isoniazid; TB, tuberculosis; UTI, urinary tract infection.

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Fungal Infections There is an association between anti-TNF therapy and invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, and pneumocystosis9,10,18,19,33 (Table 2). Certain fungal infections develop in specific geographic locations and should be considered when evaluating patients with treatment-related symptoms.35 For example, in one study, the majority of the 240 cases of histoplasmosis in patients with IBD receiving anti-TNF therapy were from the Ohio River Valley.18 Similarly, coccidioidomycosis is exclusive to the desert southwest of the United States, with rates as high as 30/100,000 patient-years.20 Our recommendations for treatment of fungal infections in the setting of anti-TNFs are identical to those for bacterial infections. The most common fungal infections in patients with IBD are the same as those in the immunocompetent host, for example, skin infections or oropharyngeal candida. These fungal infections do not require cessation of IBD immunosuppression and may be successfully treated with antifungal agents. Patients with opportunistic fungal infections should stop immunosuppression while receiving appropriate antifungal treatment. As is the case in managing opportunistic bacterial infections, it is our experience that the anti-TNF may be successfully restarted once the invasive fungal infection has been eradicated.

Viral Infections The viral infections most commonly encountered by patients with IBD are the upper respiratory viruses (“common cold”), which afflict millions of people each year (Table 3). These upper respiratory viruses do not mandate cessation of immunosuppression and are usually self-limited.36 For patients with high fever or concerns for dehydration, we suggest temporarily stopping the immunosuppression and restarting as the viral symptoms resolve. Although viral infections may occur with anti-TNFs, viruses are more prominent with the thiopurines. Viral infections may be due to reactivation or new-onset infection, for example, human papilloma, herpes simplex virus, varicella, hepatitis B, EBV, and cytomegalovirus (CMV).12,15,16,36–40

EBV is of particular concern in patients treated with thiopurines. New-onset infection and reactivation of EBV have been associated with lymphoma (see Malignancies section), mononucleosis, hepatitis, bone marrow suppression, and severe forms of hemophagocytic lymphohistiocytosis, which may result in end-organ failure and death.12,41 Although these severe events are rare, there may be justification for screening patients for EBV before initiating thiopurine therapy, especially male patients, who are at increased risk.12 Most patients older than 30 years are seropositive for EBV, but up to 30% of younger patients are seronegative.12 In male patients who are EBV negative, it may be reasonable to avoid thiopurines and consider alternative immunosuppression. We stop thiopurines and do not restart AZA/6MP in our male patients who develop new-onset EBV mononucleosis. We stop thiopurines, but will restart these agents, in our female patients who have benefited from AZA/6MP and have recovered from the acute infection. Due to EBV related infection and lymphoma, we now use methotrexate more frequently in our male patients. The HPV is a common virus that may lead to cutaneous and anogenital lesions in immunosuppressed patients with IBD. The most common cutaneous lesions are warts. In a prospective study of 230 patients, there was a significant increase in viral warts in the group receiving AZA/6MP compared with those not on immunosuppression (17.2% versus 3.3%, P ¼ 0.004).36 Similarly, another study found an increase in abnormal pap smears in patients with IBD compared with controls (42% versus 7%, P , 0.001), with HPV lesions associated with immunosuppressive medications.42 We are currently studying the impact of IBD immunosuppression on anal HPV and cancer. Given the risk of cervical cancer associated with HPV, we recommend regular gynecologic examinations for female patients with IBD and administration of the human papilloma vaccine to all patients before the initiation of immunosuppression.42,43 Generally, we do not stop immunosuppression in patients who develop HPV cutaneous warts or cervical lesions. However, if the warts become numerous, or cause disfiguration that cannot be treated with topical agents, we do stop AZA/6MP.

TABLE 2. Continue, Stop, or Restart Medications for Fungal Infections Fungal Mild Examples: Oropharyngeal or genital candida Note: Usually responsive to antifungal therapy

AZA/6MP

Continue

Anti-TNFs

Continue

CYA, cyclosporine; PCP, pneumocystis jirovecii pneumonia.

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Fungal Severe Example: Candida sepsis pneumocystis Note: Consider PCP prophylaxis in triple immunosuppression (steroid, 6MP, anti-TNF, or CYA) Stop, restart once treated only if IBD severe Stop, restart once treated only if IBD severe

Fungal Infection by Geography Example: Histoplasmosis—Ohio River Valley Coccidiomycosis—Desert Southwest Note: Currently no screening recommendations Stop, restart once treated only if IBD severe Stop, restart once treated only if IBD severe



TABLE 3. Continue, Stop, or Restart Medications for Viral Infections Viral Mild

Viral Moderate

EBV

Examples: Examples: “Common cold” viruses, -Human papilloma for example, -Varicella zoster rhinovirus -Influenza Note: Note: Supportive care Vaccinate, avoid live zovirax in immunosupp

2 scenarios: -Acute infection, Mononucleosis and hemophagocytic lymphohistiocytosis -Reactivation Note: Males more susceptible to severe infections and lymphoma

AZA/6MP

Continue

Stop

Stop, do not restart in male patients

Anti-TNFs

Continue

Continue, unless severe sequelae

Continue, unless severe sequelae or viremia

CMV 3 scenarios: 1. Colon bx +, but mild colitis (should receive anti-viral rx) 2. Colon bx +, but severe ulcers 3. Colon bx and blood + for CMV (should receive anti-viral rx) Scenario 1: continue Scenario 2 and 3: stop Scenario 1 and 2: continue Scenario 3: stop, but restart once viremia clears

bx, biopsy; rx, treatment; immunosupp, immuosuppressant.

We will also discontinue thiopurines in women with cervical HPV that cannot be eradicated or that progresses to neoplasia.41 We have found that stopping the thiopurine often leads to resolution of the HPV-related complication. In these cases, if an immunosuppressive agent is required for the IBD, we recommend anti-TNFs. In our experience, administration of anti-TNF agents has not worsened HPV or caused progression of cutaneous/genital lesions. We have also used methotrexate in this setting, but our experience is limited. Our approach to herpes simplex virus and CMV is similar to HPV. Specifically, most patients who reactivate these viruses have a mild symptom complex that does not require cessation of immunosuppression. There are patients who develop severe symptoms and sequelae of these viruses, and we recommend stopping the thiopurines in these cases. For example, CMV be may found in immunohistochemical stains of colonic biopsies from patients with UC. The challenge is to determine whether this reflects a systemic infection or is somehow reactivated in the colonic epithelium of patients with IBD without viropathic or clinical consequence.40,44 Corticosteroids and cyclosporine have been associated with CMV reactivation in patients with IBD, whereas anti-TNF agents have not.16,45 There are conflicting data regarding an association between thiopurines and CMV reactivation, with prospective studies showing no increased risk.45,46 CMV colitis is much more commonly seen in steroid refractory UC, and there have been only a few reports of CMV complicating CD.44 CMV reactivation can affect patients with IBD in at least 3 separate manners: (1) CMV infection without intestinal involvement, with systemic symptoms and CMV viremia; (2) CMV disease involving the colon, with systemic and localized evidence of CMV infection by virological testing; (3) colonic CMV infection, with no systemic or localized signs of disease.44,45 We consult with our infectious disease specialist on all of these cases. If the patient does not have significant inflammation, specifically

deep ulcers, and does not have CMV in the blood, we continue IBD treatment and do not treat the CMV. In general, antiviral therapy is indicated in patients with IBD with primary CMV infection associated with an exacerbation of colitis. In patients with severe colitis, with CMV detected in the colonic mucosa, we do recommend CMV treatment and stop the thiopurines, until colitis symptoms improve.44 In these cases, it has been our experience that the IBD may become quite active and we will use antiTNFs without worsening the CMV colitis. Finally, we recommend stopping immunomodulators in patients with CMV in the colon along with viremia. We work closely with the infectious disease specialist, but these patients may require prolonged treatment for their CMV. We have found that patients who develop CMV in the setting of UC, regardless of viremia, often have a more aggressive course of disease and have a higher rate of colectomy. Acute varicella is a rare infection in IBD but may be fatal in patients taking thiopurines.47,48 AZA/6MP must be stopped in a patient with new-onset varicella infection. Varicella zoster reactivation, or shingles, is a painful dermatologic lesion, more commonly occurring in immunosuppressed individuals and in patients with inflammatory diseases.37,49 Shingles can be associated with any immunosuppressive medication, including corticosteroids, thiopurines, and anti-TNF therapies.37,38,48 Most zoster is self-limited and does not necessarily require cessation of immunosuppression or anti-viral treatment.47,48 However, if an antiviral is started, it should be done so within 48 to 72 hours of symptom onset. For more severe lesions or zoster that involves the face, especially ocular involvement, we will stop all immunosuppression until the vesicles resolve. Reactivation of hepatitis B infection in patients receiving anti-TNF therapy is well described and has led to fulminant hepatic failure and death.15,50 Before starting an anti-TNF, hepatitis B status should be ascertained by checking hepatitis B surface www.ibdjournal.org |

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antibody, as well as surface antigen and core antibody.15,39 Most patients who have been vaccinated will have hepatitis B surface antibody as their only positive serology. If patients have not been vaccinated, this should be recommended, if possible, before initiation of anti-TNF therapy.39 If patients develop acute hepatitis B infection, or experience reactivation of disease during anti-TNF therapy, the medication should be immediately stopped, and the hepatitis B treated with antiviral therapy.15,51 Once the hepatitis B is cleared, and patients develop hepatitis B surface antibody, antiTNF therapy could be restarted if needed, based on the severity of the IBD. Patients with chronic inactive hepatitis B, at risk for reactivation during anti-TNF therapy, should receive antiviral prophylaxis.34,39 It is recommended that antiviral therapy be commenced 1 to 3 weeks before anti-TNF initiation and continued for at least 6 months beyond discontinuation of the anti-TNF agent.15,16,34,39 Although the data are limited, hepatitis C does not seem to worsen with anti-TNF treatment and we usually do not stop or alter anti-TNF therapy in these patients.16,34

Clostridium difficile Clostridium difficile infection is the most common gastrointestinal infection in patients with IBD. One study found that in a 2-year period, there was a quadrupling of C. difficile infection in patients with IBD and a nearly 5-fold increase in hospitalizations.52,53 The C. difficile–infected patient with IBD may not have classic risk factors or clinical presentation, such as recent antibiotic exposure, recent hospitalization, or pseudomembranes on endoscopic evaluation.54 It is now our practice to evaluate for C. difficile in any IBD patient with an increase in diarrhea concerning for an IBD exacerbation. To date, there is no evidence that immunosuppression with thiopurines or anti-TNF agents are linked to the increase in infection.27,55 It has been our experience that, as with CMV, C. difficile may exacerbate UC, resulting in a more refractory disease, requiring surgery. We recommend stopping or minimizing corticosteroids in the setting of infection because this class of medication may be associated with decreased response to C. difficile therapy. Due to the potential for worsening IBD, we do not stop the thiopurines or anti-TNFs and will even start biologics in combination with C. difficile treatment if the colitis is severe.

MALIGNANCIES Malignancy is the most feared consequence of immunosuppressive medications, for both patients with IBD and physicians. Fortunately, the risk of developing a malignancy related to an IBD medication is quite low. Nonetheless, patients with IBD may develop cancer, and the decision to stop or continue immunosuppressive treatment poses a management dilemma. The 2 scenarios that physicians may encounter are: (1) a patient with a history of cancer and the decision to initiate a thiopurine or anti-TNF; and (2) a new-onset malignancy while receiving immunosuppressive treatment. We have focused this section on the following malignancies: solid tumors, lymphoma, and skin cancers.

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Solid Tumors There does not seem to be an increased risk of developing a de novo solid tumor from thiopurines or anti-TNFs.11,25,56–64 A common dilemma is how to approach a patient with a history of a solid tumor who requires immunosuppression for their IBD, although there are a paucity of data to guide the physician. Most of the AZA/6MP and anti-TNF clinical trials exclude patients with active or past malignancy. However, registries, prospective, and retrospective studies have not shown a significant recurrence of cancer with thiopurines or anti-TNFs.64–66 The German biologics registry (RABBIT) in rheumatoid arthritis reported a low incidence of cancer recurrence in 5300 patients exposed to anti-TNF therapy, 124 of whom had prior malignancies.65 In the anti-TNF group, the recurrence rate was 45/1000 patient-years compared with a rate of 31/1000 patient-years in the group receiving disease-modifying anti-rheumatic drugs. This comparison showed a nonsignificant increased incidence risk ratio of 1.4 in the anti-TNF group (P ¼ 0.63). Similarly, Dixon et al66 used the British Society for Rheumatology Biologics Register to evaluate rates of recurrent malignancy in rheumatoid arthritis patients exposed to anti-TNF therapy. Of their 293 patients, 80% had a prior solid tumor, with the majority (58%) being .10 years removed from the cancer. In the group exposed to anti-TNF agents, there was an incidence rate for cancer of 25.3/1000 patient-years compared with 38.3/1000 patient-years in the disease-modifying anti-rheumatic drug group (incidence risk ratio ¼ 0.58; 0.23–1.43). When we encounter this situation, we consult with an oncologist. In the majority of cases, as long as the patient does not have active cancer or a history of metastatic disease, we initiate thiopurines and/or anti-TNFs. Methotrexate may also be a good option as this may have chemotherapeutic properties, albeit at much higher doses, and not for all cancer types. Although there are no data as to what constitutes a safe interval between cancer eradication and initiation of immunosuppression, we generally use 1 year as our cutoff point. That is, as long as the patient has been free of cancer for at least 1 year, we will initiate IBD treatment. If a malignancy develops while a patient is receiving a thiopurine or anti-TNF medication, consultation with an oncologist is mandatory (Table 4). The risk of stopping treatment and IBD exacerbation needs to be weighed against the risk of cancer progression.67 We do not stop the IBD immunosuppression in patients with localized cancer that is eradicated by resection. In contrast, it is our practice to stop the thiopurines and anti-TNFs if a solid tumor develops and requires chemotherapy. Oncologic chemotherapy may have immunosuppressive effects and is theoretical that this would also treat IBD.67 The decision on restarting the immunosuppressive IBD medications depends on the extent of cancer eradication and the severity of the CD or UC.41,67 Those patients who have been in a deep remission may do well for a period without immunosuppression, and we suggest giving them a “drug holiday.” If the patient has severe IBD while receiving chemotherapy, we will use corticosteroids during their therapy and then time the re-initiation of immunosuppression with the



TABLE 4. Continue, Stop, or Restart Medications for Malignancy

Solid Tumor

AZA/6MP

Anti-TNFs

Examples: Breast Lung Renal Note: No causality with IBD meds; methotrexate is probably safe -Continue if curative resection -Stop if mets and chemorx -Restart once chemo done and no active cancer -Continue if curative resection -Stop if mets and chemorx -Restart once chemo done and no active cancer

Lymphoma— Hepatosplenic T Cell

Lymphoma—After Acute EBV Infection

Lymphoma— Lymphoproliferative Similar to PTLD

Note: -Predominantly young males -No link to EBV -More common in combination treatment

Note: -Predominantly males -EBV negative and become infected on 6MP -Lymphoma may revert when 6MP stopped

Stop, never restart

Stop, never restart

Note: -Develops in EBV-positive pts -Linked to long-duration 6MP -Males . females -Intestinal involvement -Lymphoma may revert when 6MP stopped Stop, never restart

Stop, probably never restart

Stop, but restart once lymphoma treated

Continue, only stop if progression of lymphoma

pts, patients; meds, medications; mets, metastases; chemorx, chemotherapy.

oncologist. For our most severe patients with IBD, we have reinitiated thiopurines and anti-TNFs as early as 3 months after the cessation of chemotherapy. These patients are monitored closely in conjunction with the oncologist.

Lymphoma Aside from nonmelanoma skin cancers, lymphoma is the most significant malignancy associated with immunosuppressive treatment.6,56 Thiopurines are most associated with lymphoma, whereas anti-TNF monotherapy has significantly less risk.1,6,9,26,61,68 Thiopurines in combination with anti-TNFs increase lymphoma risk, but only marginally compared with AZA/6MP monotherapy.69 Hepatosplenic T-cell lymphoma is an exception and is associated with higher risk from the combination of medications.70 The risk of lymphoma is increased with prolonged use of immunosuppression and older age.6,71 The risk may be up to 5-fold higher in patients administered thiopurines compared with those not on immunosuppression.6,63,68,71,72 Stopping the thiopurine reduces the risk of lymphoma to that of the general population.6,71 When confronted with a patient who has a remote history of non-Hodgkin’s lymphoma and develops IBD, we avoid AZA/6MP and use methotrexate and anti-TNFs. The 3 IBD treatment-related lymphoma subtypes are associated with age, gender, duration of treatment, and EBV status12 (Table 4). The lymphoma types may be stratified to a young onset (younger than 30 years) and an older onset (older than 30 years). Based on these factors, the IBD-related lymphomas, in increasing order of prevalence include: (1) young males with hepatosplenic T-cell lymphoma, independent of EBV; (2) young males with acute EBV infection; and (3) older patients with EBV-positive lymphoproliferative disease.12,63,73

The hepatosplenic T-cell lymphoma is an extremely rare (0.05/1000 patient-years), uniformly fatal lymphoma that is not related to EBV.12,70 Most of the cases have been reported in men younger than 30 years receiving the combination of an anti-TNF and thiopurine therapies. There are cases of hepatosplenic T-cell lymphoma with thiopurine therapy alone but not with anti-TNF or methotrexate monotherapy.70 This type of lymphoma typically occurs when the patient has been on prolonged combination treatment for more than 2 years.70 We have not encountered this type of lymphoma in our practice, but the immunosuppression must be stopped and not restarted. Although there are no data to guide post-hepatosplenic T-cell lymphoma IBD treatment, if a patient survives the lymphoma, a thiopurine should never be used again, and anti-TNF therapy should probably be avoided. In our practice, we are lowering and stopping AZA/6MP after 1 year in young men who achieve a deep remission on combination therapy.41 However, for those male patients with particularly disabling IBD, we do not stop the thiopurine but will lower the dose. Whether a lower dose thiopurine reduces the risk of lymphoma and is protective against anti-TNF–related immunogenicity is not known. The second type of lymphoma related to IBD immunosuppression occurs in males younger than 30 years who are initially seronegative for EBV and develop an acute infectious mononucleosis in the setting of AZA/6MP.12,14 This acute EBV-related lymphoma is rare in the overall IBD population (0.1/1000 patientyears) but is much more common if the patient is male (3/1000 patient-years).6 The lymphoma often occurs shortly after the mononucleosis develops, is similar to the X-linked lymphoproliferative disease, and is often fatal.12,41 When a young male patient develops an acute EBV mononucleosis, we stop the thiopurine www.ibdjournal.org |

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TABLE 5. Continue, Stop, or Restart Medications for Skin Cancers

AZA/6MP

Anti-TNFs

Basal Cell

Squamous Cell

-Associated with 6MP and sun exposure -Does not regress when 6MP stopped -Methotrexate is probably safe -Continue unless numerous or disfiguring lesions -Stop if numerous or disfiguring lesions -Do not restart -Continue, no association with anti-TNF

-Associated with 6MP and sun exposure -Does not regress when 6MP stopped -Methotrexate is probably safe -Continue unless numerous or disfiguring lesions -Stop if numerous or disfiguring lesions -Do not restart -Continue, no association with anti-TNF

and do not use AZA/6MP for their IBD treatment. Although we have not yet routinely tested EBV serology before starting thiopurines, this is a consideration.12 Male patients who are EBV seronegative, that is, immunoglobulin G and M negative, would be considered for treatment with something other than AZA/6MP. The final type of IBD-related lymphoma is similar to the posttransplant lymphoproliferative disease (PTLD).12 These patients are usually older than 30 years and seropositive for EBV. Unlike the acute EBV mononucleosis lymphoma, these patients have been exposed to EBV in the past and have immunoglobulins to EBV. The similarity to PTLD is that these are primarily intestinal lymphomas that occur at a site of previous inflammation.41 The distinction from PTLD, which occurs shortly after transplant immunosuppression, is that the EBV-positive IBD-related intestinal lymphoma occurs with advancing age and a longer duration of thiopurine exposure.12,71 There does tend to be a male predominance, but females may also be affected. This lymphoma is usually reversible with cessation of AZA/6MP.14 In our practice, if a patient develops PTLD-like lymphoma on AZA/6MP, we immediately stop this agent and do not restart. It has been our experience that most of these lymphomas are indolent and do not require treatment beyond cessation of thiopurines. In our older male patients who have been on thiopurines for a long duration, and are in remission, we tend to decrease the thiopurine dose and individualize the risks and benefits of stopping treatment.

Skin Cancer The nonmelanoma skin cancers, basal and squamous cell cancers, are the most common cancers in the United States. The annual incidence of nonmelanoma skin cancers continues to increase, and although associated with low mortality, these lesions can be destructive and disfiguring. There is a well-established association between immunosuppression and nonmelanoma skin cancers.12,13,56,74,75 The risk of squamous cell cancer in posttransplant patients is approximately 65 to 250· that of the general population, and there is also at least a 10· increased risk of basal cell cancer with immunosuppression.76,77 Due to the increased rate

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Melanoma -Slight increased risk with 6MP and anti-TNF -Sun exposure -Continue if curative resection and close dermatology follow-up -Stop if metastatic disease or recurrent lesions -Continue if curative resection and close dermatology follow-up -Stop if metastatic disease or recurrent lesions

of skin diseases in patients with IBD, we recommend at least one full skin examination by a dermatologist in any patient on immunosuppression, although preferably on an annual basis.41,78 The rates of basal cell and squamous cell cancer are highest with AZA/6MP and less increased with anti-TNFs.13,41,74,75,79–81 Older age, previous sun exposure, and longer duration of thiopurine use are associated with nonmelanoma skin cancers.13 Unlike lymphoma, stopping AZA/6MP does not eradicate the skin cancer, and patients remain at risk for developing new basal/squamous cell cancers even after discontinuation of therapy.13 Development of melanoma is slightly increased with both AZA/ 6MP and anti-TNF agents.74,82 However, the association with immunosuppression is less pronounced, and less well characterized, compared with basal cell and squamous cell cancers. It is our practice to recommend sun protection and dermatologic screening in our patients with IBD on AZA/ 6MP.78 If patients have a history of previous nonmelanoma skin cancer, we weigh the risk and benefit of AZA/6MP based on the severity and activity of cancer (Table 5). In any case of nonmelanoma skin cancer, methotrexate and/or anti-TNFs may be started in conjunction with close dermatologic follow-up. We will continue AZA/6MP in those patients who develop basal cell or squamous cancers on AZA/6MP if they have limited lesions that are easily treated by the dermatologist. However, our experience is that many of these patients will develop numerous, aggressive, and sometimes disfiguring lesions that require cessation of AZA/6MP. Although the risk of skin cancers does not resolve with discontinuation of thiopurines, it has been our experience that there is a degree of regression. If the AZA/6MP is stopped, and ongoing immunosuppression is required, we use methotrexate and antiTNFs and have not experienced progression of skin cancer. Patients who have a history of melanoma should avoid immunosuppression for at least 2 years after the skin cancer has been eradicated, although this decision needs to be made in close collaboration with a dermatologist. We recommend stopping all immunosuppression in patients who develop a de novo melanoma, while being treated. If the melanoma is eradicated, then we will wait at least 2 years


before restarting any immunosuppression, although we work very closely in these cases with our dermatology colleagues. Any patient with metastatic melanoma should not restart immunosuppression.

PUTTING RISK IN PERSPECTIVE The majority of side effects associated with thiopurines and anti-TNFs are mild, self-limited, and reversible. Serious infections, lymphoma, and skin cancers rarely occur with these medications but merit consideration in any patient starting treatment. It is important to involve the patient in the decisionmaking process and put the risks of medication side effects in perspective.2,83 For example, the risk of a lymphoma developing on AZA/6MP (4/10,000 patient-years) is comparable with the lifetime risk of dying from drowning (1/1112) or dying in a bicycle accident (1/5000). The risk is much less than the risk of dying in an automobile accident (1/108).84 Patients are willing to accept risks of serious infection, lymphoma, and even progressive multifocal leukoencephalopathy if their disease is severe and the chance of a clinical response outweighs the risk.2,85 Gender, age, and geographical location may influence decisions on medications for patients with IBD. Male patients are more likely than female patients to develop lymphoma on AZA/ 6MP, especially after acute mononucleosis or in combination with an anti-TNF therapy (hepatosplenic T-cell lymphoma).14,69,70 A negative Epstein–Barr serology in a young male patient may influence the decision toward non-thiopurine-based treatment. Similarly, stopping the thiopurine after 1 to 2 years of anti-TNF combination therapy may avoid the risk of hepatosplenic T-cell lymphoma and PTLD-like lymphoma but still prevent immunogenicity. Patients older than 65 years are more susceptible to opportunistic infections and cancer. However, if immunosuppression is required, this may be a group that monotherapy with AZA/6MP or anti-TNF therapy would be warranted, with cessation of treatment after remission is achieved. At present, the geographical location of a patient has not influenced the decision on which treatment to initiate. Patients from endemic regions of tuberculosis infection require careful screening and treatment of latent infection before initiation of anti-TNFs. Due to the high rates of skin cancer with immunosuppression, patients who live in regions of high sun exposure should have dermatologic monitoring and be considered for non-thiopurinebased treatment. The decision to modify or stop treatment in patients in deep remission for a prolonged time has not been well established. It has been our practice to lower the concomitant AZA/ 6MP in patients on combination therapy with anti-TNF and then to stop the thiopurine in patients in deep remission for 3 years. However, this decision must be individualized, and for patients with severe, disabling disease, we generally do not alter treatment. Patients who develop an infection or malignancy on IBD treatment may be able to continue the medications during treatment of the complication, or stop and then restart their immunosuppression, once the infection resolves. Most mild viral, bacterial, and fungal infections do not require cessation of treatment. Severe infections, especially opportunistic infections,


warrant medication cessation, with resumption of treatment once the infection is cleared. Solid tumors have not been associated with IBD treatment. If a solid tumor develops in a patient receiving AZA/6MP/anti-TNF, the immunosuppression may be continued for cancers that are contained and easily resected but should be stopped in patients with metastatic disease or in patients undergoing chemotherapy. Once the cancer is eradicated and chemotherapy stopped, usually the thiopurine or antiTNF may be resumed. The development of a lymphoma mandates discontinuation of immunosuppression. The posttransplant-like intestinal lymphomas may resolve without chemotherapy once the thiopurine is stopped. In contrast, the hepatosplenic T-cell lymphomas are usually fatal and do not resolve with AZA/6MP cessation. We try to avoid future immunosuppression in patients with lymphoma, but if the IBD is severe and warrants aggressive treatment, we favor methotrexate and anti-TNFs rather than thiopurines. Each patient with CD and UC has a distinctly unique phenotype. Similarly, the development of an infection or malignancy in an IBD patient should be approached as an individual event. To that end, when a medication side effect develops in a patient, the treating physician will need to make a decision on continuing, stopping, or restarting IBD treatment based on that patient’s history of IBD and individual circumstances at the time of the event. Taking a multidisciplinary team approach and including specialists from other fields is imperative in the management of these complex cases.

ACKNOWLEDGMENTS The authors would like to thank Corey Siegel, MD, and Lisa Grandinetti, MD, for their assistance in the preparation of this manuscript.

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Does a personal or family history of malignancy preclude the use of immunomodulators and biologics in IBD.

Restarting biologics and management of patients with flares of inflammatory rheumatic disorders or psoriasis during active tuberculosis treatment.

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Primary hyperparathyroidism and malignancy: Forgotten friends or new aquaintances.

Continuing aspirin therapy during percutaneous nephrolithotomy: unsafe or under-utilized?

When and How to Treat HCV Infection with the New Antivirals before or after Liver Transplantation.

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LK or IGF1R: When selectivity hurts.

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