Balancing Benefit vs Risk of Immunosuppressive Therapy for Individual Patients With Inflammatory Bowel Diseases
2018; Elsevier BV; Volume: 17; Issue: 3 Linguagem: Inglês
10.1016/j.cgh.2018.07.013
ISSN1542-7714
AutoresLaurent Beaugerie, Julien Kirchgesner,
Tópico(s)Eosinophilic Esophagitis
ResumoInflammatory bowel diseases (IBD) and their treatments, particularly immunosuppressive drugs, increase risk of infections and cancers. However, by promoting mucosal healing, these agents should reduce risks of infections related to intestinal lesions, malnutrition, intravenous devices, and IBD surgeries and reduce risk of cancers associated with chronic mucosal inflammation—although there are few data to support this concept. Corticosteroids increase the risk of vascular thromboembolic events, yet other immunosuppressive drugs that induce deep remission from IBD could decrease the incidence of cardiovascular events attributable to systemic inflammation and IBD-related hospitalizations and/or surgeries. The nature and magnitude of the risks of infections and cancers vary with immunosuppressive drug class and patient sex and age. For example, thiopurines increase risk of viral infections that might be fatal in young patients, whereas tumor necrosis factor antagonists increase risk of bacterial and intracellular infections that can be fatal in patients of any age, but particularly in older patients. The ability of drugs to prevent IBD-associated colorectal cancer varies with IBD location and duration. Models to assess the benefit:risk ratio of long-term use of immunosuppressive drugs for patients with IBD should be adapted based on patients’ age, sex, and IBD phenotype, to properly guide patient management. The decision-making process should begin with a clear explanation of treatment risks and then integrate the patient’s emotional perception of risks. Inflammatory bowel diseases (IBD) and their treatments, particularly immunosuppressive drugs, increase risk of infections and cancers. However, by promoting mucosal healing, these agents should reduce risks of infections related to intestinal lesions, malnutrition, intravenous devices, and IBD surgeries and reduce risk of cancers associated with chronic mucosal inflammation—although there are few data to support this concept. Corticosteroids increase the risk of vascular thromboembolic events, yet other immunosuppressive drugs that induce deep remission from IBD could decrease the incidence of cardiovascular events attributable to systemic inflammation and IBD-related hospitalizations and/or surgeries. The nature and magnitude of the risks of infections and cancers vary with immunosuppressive drug class and patient sex and age. For example, thiopurines increase risk of viral infections that might be fatal in young patients, whereas tumor necrosis factor antagonists increase risk of bacterial and intracellular infections that can be fatal in patients of any age, but particularly in older patients. The ability of drugs to prevent IBD-associated colorectal cancer varies with IBD location and duration. Models to assess the benefit:risk ratio of long-term use of immunosuppressive drugs for patients with IBD should be adapted based on patients’ age, sex, and IBD phenotype, to properly guide patient management. The decision-making process should begin with a clear explanation of treatment risks and then integrate the patient’s emotional perception of risks. Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by continuous or relapsing intestinal inflammation. Both inflammatory bowel diseases (IBDs) are lifetime diseases. Most of the treatments that are currently used are anti-inflammatory drugs. These anti-inflammatory drugs, except 5-amino-salicylates, also exhibit immunosuppressive properties. Immunosuppressive drugs that are used for the treatment of IBD include small molecules (corticosteroids, thiopurines, and methotrexate) and biologics (anti–tumor necrosis factor [TNF] agents, vedolizumab, and ustekinumab). New biologics and immunosuppressive small molecules (Janus kinase [JAK] inhibitors and Sphingosine 1 phosphate receptor modulators) are under development. Because of the possible complications of immunosuppression, clinicians do not consider using these drugs on a lifetime basis. There is a growing trend toward a cyclic use of these drugs. When making the decision to enter a therapeutic cycle, clinicians and patients are interested in benefit-risk balance modeling studies, which should ideally integrate all benefits and risks associated with therapeutic strategies. This research area is recent in IBD. Major advances occurred within the last years because of growing access to medicoadministrative databases and initiation of well-phenotyped observational cohorts. In westernized countries, the 2 primary causes of death are cardiovascular disease and cancer.1Heron M. Anderson R.N. Changes in the leading cause of death: recent patterns in heart disease and cancer mortality.NCHS Data Brief. 2016; : 1-8PubMed Google Scholar This is also true for individuals living with IBD.2Jess T. Frisch M. Simonsen J. Trends in overall and cause-specific mortality among patients with inflammatory bowel disease from 1982 to 2010.Clin Gastroenterol Hepatol. 2013; 11: 43-48Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar In developed countries, death by infection (mainly influenza and pneumonia) is 20 times less frequent than death by cancer.3Murphy S.L. Xu J. Kochanek K.D. et al.Deaths: final data for 2015.Natl Vital Stat Rep. 2017; 66: 1-75PubMed Google Scholar Patients with IBD may develop cancers, cardiovascular events, and infections that are not related to IBD or IBD treatment, are attributable to IBD itself, or are attributable to IBD treatment. Immunosuppressive drugs have been shown to promote immunosuppression-related infections and cancers (Figure 1). Via mucosal healing, immunosuppressants are also candidates for reducing the incidence of infections related to IBD. Finally, with the exception of corticosteroids that increase the risk of vascular thromboembolic events, it is plausible that immunosuppressive drugs that lead to IBD deep remission could decrease the incidence of cardiovascular events attributable to IBD. The association between treatment exposure and outcomes of interest may be expressed in relative terms, such as relative risks or odds ratios. The absolute risk is the probability of the occurrence of a specified outcome within a period of time (incidence rate). Incidence rates are generally expressed as the number of events per patient-years. The denominator of 1000 persons-years is increasingly used in the IBD literature. The number of events per 1000 years represents the risk percentage of developing the event for a 10-year period. For physicians, absolute and relative risks are complementary approaches for the integration of medical knowledge. In contrast, when considering an individual patient in clinical practice, absolute risks are exclusively relevant for determining the individual benefit-risk balance of a therapeutic strategy. Figure 2 plots the magnitudes of the risks of key events that may be observed in individuals with IBD on a logarithmic scale. For each event category, numbers are the sum of events not related to IBD or IBD treatment, related to IBD, or related to IBD treatment. The qualifying adjectives that appear in the figure are those used by drug agencies for stratifying the magnitude of risks of adverse events associated with the use of new drugs.4Anon. Guidelines for preparing core clinical-safety information on drugs: report of CIOMS Working Group III • Council for International Organizations of Medical Sciences. Available at: https://cioms.ch/shop/product/guidelines-preparing-core-clinical-safety-information-drugs-report-cioms-working-group-iii/. Accessed February 21, 2018.Google Scholar The incidence of frequent events in IBD may be adequately estimated in reports from IBD centers or meta-analyses of randomized controlled trials. To estimate the risks of rare events, such as opportunistic infections or cancers, the minimum time of observation needed often exceeds 30,000 patient-years. This power may be attained in studies from medicoadministrative databases or observational cohorts. Subgroup assessment of the risks according to age-class and gender is possible in all studies. However, differential assessment of risks according to IBD phenotype is not possible in studies from most of the medicoadministrative databases because data on IBD phenotype are lacking. To fill in this gap, data on IBD phenotype are recorded in dedicated prospective observational cohorts, such as CESAME or I-CARE ((Ibd CAncer and seRious infections in Europe, https://clinicaltrials.gov/ct2/show/NCT02377258). Infections are extremely frequent in everyday life and can be categorized according to their clinical impact (Table 1). Serious infections are generally defined as infections that require hospitalization and may be life-threatening or result in permanent disability. In the IBD population, the incidence of serious infections ranges from 10 to 100 events per 1000 patient-years according to study designs and care pathway specificities.5Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar, 6Nyboe Andersen N. Pasternak B. Friis-Moller N. et al.Association between tumour necrosis factor-alpha inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.BMJ. 2015; 350: h2809Crossref PubMed Scopus (94) Google Scholar, 7Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry.Clin Gastroenterol Hepatol. 2006; 4: 621-630Abstract Full Text Full Text PDF PubMed Scopus (827) Google ScholarTable 1Classification of Infections That May Occur in Patients With Inflammatory Bowel DiseaseTypeDefinitionImpactBenign infections (eg, cold, oral herpes flare)Are not life-threateningDo not require hospitalizationIf repeated, may impair quality of lifeSerious infections (eg, intra-abdominal abscess, severe pneumonitis)Require hospitalization and/or result in permanent disabilityMay be life-threateningOpportunistic infections (eg, aspergillosis, severe forms of varicella)Occur selectively or are particularly severe in immunocompromised patientsAre life-threatening Open table in a new tab Opportunistic infections occur selectively or are particularly severe in immune-compromised patients, and these infections are life-threatening. There is no universal list of opportunistic infections, and infections considered in the analyses vary among studies.6Nyboe Andersen N. Pasternak B. Friis-Moller N. et al.Association between tumour necrosis factor-alpha inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.BMJ. 2015; 350: h2809Crossref PubMed Scopus (94) Google Scholar, 8Toruner M. Loftus E.V. Harmsen W.S. et al.Risk factors for opportunistic infections in patients with inflammatory bowel disease.Gastroenterology. 2008; 134: 929-936Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar Notably, the same infectious agent (eg, zoster) may cause benign, serious, or opportunistic infections according to host and context specificities and disease severity. The excess risk of infection in patients with IBD exposed to corticosteroids, thiopurines, and anti-TNF varies among types of infection and drug classes (Table 2). Few data exist on everyday benign infections. It was reported in a prospective cohort of outpatients with IBD that exposure to thiopurines was associated with an increased incidence of skin herpes flares and skin viral warts.9Seksik P. Cosnes J. Sokol H. et al.Incidence of benign upper respiratory tract infections, HSV and HPV cutaneous infections in inflammatory bowel disease patients treated with azathioprine.Aliment Pharmacol Ther. 2009; 29: 1106-1113Crossref PubMed Scopus (71) Google Scholar The incidence of zoster is intrinsically increased in patients with IBD.10Gupta G. Lautenbach E. Lewis J.D. Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease.Clin Gastroenterol Hepatol. 2006; 4: 1483-1490Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 11Long M.D. Martin C. Sandler R.S. et al.Increased risk of herpes zoster among 108 604 patients with inflammatory bowel disease.Aliment Pharmacol Ther. 2013; 37: 420-429Crossref PubMed Scopus (132) Google Scholar, 12Khan N. Patel D. Trivedi C. et al.Overall and comparative risk of herpes zoster with pharmacotherapy for inflammatory bowel diseases: a nationwide cohort study.Clin Gastroenterol Hepatol. 2018; 16: 1919-1927Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Exposure to corticosteroids, thiopurines, and/or anti-TNF agents further increases this risk.10Gupta G. Lautenbach E. Lewis J.D. Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease.Clin Gastroenterol Hepatol. 2006; 4: 1483-1490Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 11Long M.D. Martin C. Sandler R.S. et al.Increased risk of herpes zoster among 108 604 patients with inflammatory bowel disease.Aliment Pharmacol Ther. 2013; 37: 420-429Crossref PubMed Scopus (132) Google Scholar, 12Khan N. Patel D. Trivedi C. et al.Overall and comparative risk of herpes zoster with pharmacotherapy for inflammatory bowel diseases: a nationwide cohort study.Clin Gastroenterol Hepatol. 2018; 16: 1919-1927Abstract Full Text Full Text PDF PubMed Scopus (83) Google ScholarTable 2Excess Risk of Infection and Infection-Related Mortality in Patients With IBD Exposed to Corticosteroids, Thiopurines, and Anti-TNF Agents Compared With Patients Not Exposed to Immunosuppressive DrugsIncidence rate (cases per 1000 person-years) in total IBD populationAdjusted HR (95% CI) in patients with IBD exposed to immunosuppressive therapy versus those not exposed to immunosuppressive therapyThiopurines aloneAnti-TNF agents aloneThiopurines in combination with anti-TNF agentsBenign infections OverallNDNDNDND ZosteraData from Khan et al.127.61.5 (1.3–3.7)1.2 (0.9–1.4)1.7 (1.2–2.2)Serious infections9.8bData from Kirchgesner et al.51.3 (1.2–1.4)bData from Kirchgesner et al.51.6 (1.0–2.6)cData from Nyboe-Andersen et al.62.8 (2.4–3.2)bData from Kirchgesner et al.5Opportunistic infections OverallbData from Kirchgesner et al.50.83.7 (3.0–4.6)4.0 (3.1–5.3)7.9 (5.40–11.4) ViralbData from Kirchgesner et al.50.39.0 (6.6–12.3)5.2 (3.2–8.3)10.2 (5.5–19.0) BacterialbData from Kirchgesner et al.50.21.9 (1.1–3.3)4.5 (2.7–7.4)9.0 (4.5–18) Fungal0.2dData from Lichstentein et al.171.5 (0.7–3.6)bData from Kirchgesner et al.51.9 (0.8–4.8)bData from Kirchgesner et al.51.5 (0.4–5.7)bData from Kirchgesner et al.5Infection-related mortality0.4bData from Kirchgesner et al.5NDNDNDCI, confidence interval; HR, hazard ratio; IBD, inflammatory bowel disease; ND, no data; TNF, tumor necrosis factor.a Data from Khan et al.12Khan N. Patel D. Trivedi C. et al.Overall and comparative risk of herpes zoster with pharmacotherapy for inflammatory bowel diseases: a nationwide cohort study.Clin Gastroenterol Hepatol. 2018; 16: 1919-1927Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholarb Data from Kirchgesner et al.5Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholarc Data from Nyboe-Andersen et al.6Nyboe Andersen N. Pasternak B. Friis-Moller N. et al.Association between tumour necrosis factor-alpha inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.BMJ. 2015; 350: h2809Crossref PubMed Scopus (94) Google Scholard Data from Lichstentein et al.17Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry.Am J Gastroenterol. 2012; 107: 1409-1422Crossref PubMed Scopus (601) Google Scholar Open table in a new tab CI, confidence interval; HR, hazard ratio; IBD, inflammatory bowel disease; ND, no data; TNF, tumor necrosis factor. A similar excess risk of serious infections in patients exposed to monotherapies with thiopurines and anti-TNF agents was reported in a meta-analysis of randomized controlled trials.13Bonovas S. Fiorino G. Allocca M. et al.Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis.Clin Gastroenterol Hepatol. 2016; 14: 1385-1397Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar The excess risk primarily relates to viral infections in patients exposed to monotherapy with thiopurines.5Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar The risk of serious infections is even higher in patients exposed to corticosteroids or combination therapy with thiopurines and anti-TNF agents.5Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar, 14Lewis J.D. Scott F.I. Brensinger C.M. et al.Increased mortality rates with prolonged corticosteroid therapy when compared with antitumor necrosis factor-α-directed therapy for inflammatory bowel disease.Am J Gastroenterol. 2018; 113: 405-417Crossref PubMed Scopus (83) Google Scholar There is an excess risk of opportunistic infections in patients exposed to monotherapies with thiopurines and anti-TNF agents.5Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar, 6Nyboe Andersen N. Pasternak B. Friis-Moller N. et al.Association between tumour necrosis factor-alpha inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.BMJ. 2015; 350: h2809Crossref PubMed Scopus (94) Google Scholar, 8Toruner M. Loftus E.V. Harmsen W.S. et al.Risk factors for opportunistic infections in patients with inflammatory bowel disease.Gastroenterology. 2008; 134: 929-936Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar, 13Bonovas S. Fiorino G. Allocca M. et al.Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis.Clin Gastroenterol Hepatol. 2016; 14: 1385-1397Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 15Ford A.C. Peyrin-Biroulet L. Opportunistic infections with anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials.Am J Gastroenterol. 2013; 108: 1268-1276Crossref PubMed Scopus (266) Google Scholar, 16Salmon-Ceron D. Tubach F. Lortholary O. et al.Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry.Ann Rheum Dis. 2011; 70: 616-623Crossref PubMed Scopus (230) Google Scholar This risk is significantly higher in patients exposed to corticosteroids7Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry.Clin Gastroenterol Hepatol. 2006; 4: 621-630Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar, 14Lewis J.D. Scott F.I. Brensinger C.M. et al.Increased mortality rates with prolonged corticosteroid therapy when compared with antitumor necrosis factor-α-directed therapy for inflammatory bowel disease.Am J Gastroenterol. 2018; 113: 405-417Crossref PubMed Scopus (83) Google Scholar, 17Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry.Am J Gastroenterol. 2012; 107: 1409-1422Crossref PubMed Scopus (601) Google Scholar or combination therapy with thiopurines and anti-TNF agents.5Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar There is an excess risk of all types of infections in patients exposed to corticosteroids and/or anti-TNF agents, particularly older patients.17Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry.Am J Gastroenterol. 2012; 107: 1409-1422Crossref PubMed Scopus (601) Google Scholar, 18Cottone M. Kohn A. Daperno M. et al.Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease.Clin Gastroenterol Hepatol. 2011; 9: 30-35Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar In contrast, the excess risk primarily relates to viral infections in patients exposed to thiopurines.5Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar There is no excess mortality from infection at the population level in patients with IBD exposed to thiopurines and anti-TNF agents,7Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry.Clin Gastroenterol Hepatol. 2006; 4: 621-630Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar, 17Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry.Am J Gastroenterol. 2012; 107: 1409-1422Crossref PubMed Scopus (601) Google Scholar, 19Hutfless S.M. Weng X. Liu L. et al.Mortality by medication use among patients with inflammatory bowel disease, 1996-2003.Gastroenterology. 2007; 133: 1779-1786Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar but some studies have reported an excess mortality from infection in patients exposed to corticosteroids.7Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry.Clin Gastroenterol Hepatol. 2006; 4: 621-630Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar, 14Lewis J.D. Scott F.I. Brensinger C.M. et al.Increased mortality rates with prolonged corticosteroid therapy when compared with antitumor necrosis factor-α-directed therapy for inflammatory bowel disease.Am J Gastroenterol. 2018; 113: 405-417Crossref PubMed Scopus (83) Google Scholar, 17Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry.Am J Gastroenterol. 2012; 107: 1409-1422Crossref PubMed Scopus (601) Google Scholar At an individual level, thiopurine-associated fatal infections have been reported mainly in young patients. These infections include severe forms of varicella20Springfeld C. Sauerbrei A. Filusch A. et al.Fatal varicella in an immunocompromised adult associated with a European genotype E2 variant of varicella zoster virus.J Clin Virol. 2009; 44: 70-73Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar and primary Epstein-Barr virus or cytomegalovirus infections complicated with hemophagocytic lymphohistiocytosis.21Biank V.F. Sheth M.K. Talano J. et al.Association of Crohn’s disease, thiopurines, and primary Epstein-Barr virus infection with hemophagocytic lymphohistiocytosis.J Pediatr. 2011; 159: 808-812Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar In patients exposed to anti-TNF agents, fatal cases of infections are related to various types of opportunistic infections.16Salmon-Ceron D. Tubach F. Lortholary O. et al.Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry.Ann Rheum Dis. 2011; 70: 616-623Crossref PubMed Scopus (230) Google Scholar There are no data on the risk of infection in patients exposed to monotherapy with methotrexate in IBD. The first safety reports on vedolizumab in patients with IBD do not suggest an increased risk of serious infections.22Colombel J.-F. Sands B.E. Rutgeerts P. et al.The safety of vedolizumab for ulcerative colitis and Crohn’s disease.Gut. 2017; 66: 839-851Crossref PubMed Scopus (561) Google Scholar Data on infections in patients with IBD exposed to ustekinumab are lacking. However, no evidence of excess infections in patients receiving ustekinumab for psoriasis was reported.23Yiu Z.Z.N. Exton L.S. Jabbar-Lopez Z. et al.Risk of serious infections in patients with psoriasis on biologic therapies: a systematic review and meta-analysis.J Invest Dermatol. 2016; 136: 1584-1591Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Patients exposed to JAK inhibitors for UC are at substantial increased risk of herpes zoster, giving sense to vaccination strategies.24Colombel J.-F. Herpes zoster in patients receiving JAK inhibitors for ulcerative colitis: mechanism, epidemiology, management, and prevention.Inflamm Bowel Dis. 2018; 24: 2173-2182Crossref PubMed Scopus (76) Google Scholar In controlled trials, patients exposed to immunosuppressive drugs who achieve mucosal healing should be at reduced risk of infections related to intestinal lesions compared with patients with uncontrolled disease. Patients exposed to thiopurines and/or anti-TNF exhibit an increased risk of immunosuppressive drug-related infections. These counterbalancing effects result in an overall similar incidence of infections in patients exposed to placebo and anti-TNF agents and/or thiopurines.13Bonovas S. Fiorino G. Allocca M. et al.Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis.Clin Gastroenterol Hepatol. 2016; 14: 1385-1397Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 25Lichtenstein G.R. Diamond R.H. Wagner C.L. et al.Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials.Aliment Pharmacol Ther. 2009; 30: 210-226Crossref PubMed Scopus (195) Google Scholar The excess risk of cancer in patients with IBD exposed to corticosteroids, thiopurines, and anti-TNF agents varies among organs and drug classes (Table 3). Patients with IBD exposed to thiopurines exhibit a mild overall excess risk of cancers.26Pasternak B. Svanström H. Schmiegelow K. et al.Use of azathioprine and the risk of cancer in inflammatory bowel disease.Am J Epidemiol. 2013; 177: 1296-1305Crossref PubMed Scopus (167) Google Scholar All patients with IBD treated with thiopurines are at increased risk of Epstein-Barr virus–associated lymphoma.27Kotlyar D.S. Lewis J.D. Beaugerie L. et al.Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis.Clin Gastroenterol Hepatol. 2015; 13 (quiz e48–50): 847-858Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar Young patients, particularly males, are at risk of postmononucleosis lymphomas and hepatosplenic T-cell lymphomas.28Beaugerie L. Itzkowitz S.H. Cancers complicating inflammatory bowel disease.N Engl J Med. 2015; 373: 195PubMed Google Scholar, 29Annese V. Beaugerie L. Egan L. et al.European evidence-based consensus: inflammatory bowel disease and malignancies.J Crohns Colitis. 2015; 9: 945-965Crossref PubMed Scopus (298) Google Scholar Patients with IBD exposed to thiopurines exhibit an increased risk of nonmelanocytic skin cancers,30Long M.D. Martin C.F. Pipkin C.A. et al.Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease.Gastroenterology. 2012; 143: 390-399Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 31Peyrin-Biroulet L. Khosrotehrani K. Carrat F. et al.Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease.Gastroenterology. 2011; 141: 1621-1628Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar and patients exposed to anti-TNF agents are at increased risk of melanoma.30Long M.D. Martin C.F. Pipkin C.A. et al.Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease.Gastroenterology. 2012; 143: 390-399Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar Older men with IBD exposed to thiopurines are at increased risk of urinary tract cancers.26Pasternak B. Svanström H. Schmiegelow K. et al.Use of azathioprine and the risk of cancer in inflammatory bowel disease.Am J Epidemiol. 2013; 177: 1296-1305Crossref PubMed Scopus (167) Google Scholar, 32Bourrier A. Carrat F. Colombel J.-F. et al.Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.Aliment Pharmacol Ther. 2016; 43: 252-261Crossref PubMed Scopus (100) Google Sc
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