Adverse Events Dig Dis 2013;31:374–378 DOI: 10.1159/000354703
Adverse Events of Tumor Necrosis Factor Inhibitors Klaus Fellermann Division of Gastroenterology, Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany
Abstract Background/Aims: Adverse events in anti-TNF treatment can be divided into allergic reactions with an acute and delayed onset, infectious complications in relation to the underlying disease, and without. Last but not least, there is the unresolved question of tumor induction and propagation. All of these may account for morbidity and eventually mortality. Methods: Literature-based review to update current knowledge about safety and adverse events of TNF blockers. Results: Major drawbacks are infectious complications with the use of anti-TNF-α antibodies. The risk is increased in inflammatory bowel disease in general and in the perioperative setting of Crohn’s disease patients. The number of tuberculosis cases has decreased since meticulous testing prior to treatment start is mandatory. An excess mortality that has been reported from referral centers is neither documented in randomized controlled trials nor in real-life settings. Regarding malignancies, lymphoma and skin cancer are a concern. The incidence of lymphoma may be raised, but this has also been debated with the use of thiopurines. Skin cancer, especially melanoma, is more common in inflammatory bowel disease and may be associated with the use of biolog-
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0374$38.00/0 E-Mail [email protected] www.karger.com/ddi
ics. Overall, most studies do not address the influence of active inflammation or co-administration of other drugs. Hence, the risk attributable to TNF blockers alone is currently ill-defined. Conclusion: Treatment with anti-TNF-α antibodies is an option with substantial risks. Most problems can be prevented by thorough workup of the patient. © 2013 S. Karger AG, Basel
Introduction
Several years have passed since the approval of the first anti-TNF-α antibody for inflammatory bowel disease (IBD) in 1998. The data basis regarding safety and efficacy is getting more robust now overlooking more than a decade of treatment for diverse diseases. As not all available antibodies have been licensed at the same time, some disparity in the datasets is obvious. In the following, current knowledge of safety issues is presented. In the end the reader has to make his/her own assumptions about the risk-benefit ratio of these biologics and if he/she, the physician as well as the patient are willing to take the risks accompanied with the drug. It has been shown that patients underestimate the burden of anti-TNF-α treatment, pointing to the necessity to properly inform the patient [1, 2].
Prof. Dr. med. Klaus Fellermann Medical Department I, UK-SH Campus Lübeck Ratzeburger Allee 160 DE–23538 Lübeck (Germany) E-Mail klaus.fellermann @ uksh.de
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Key Words Adverse events · Anti-TNF-α · Inflammatory bowel disease · Mortality · Morbidity · Cancer · Infection
Allergy is mostly related to the immunogenicity of the antibody. Due to its chimeric nature, infliximab is more prone to the occurrence of acute as well as delayed infusion reactions. However, all antibodies are proteins with an allergic potential, either administered by the intravenous or subcutaneous route. The infusion reactions can be divided in acute and delayed ones, the former starting immediately up to 4 h, the latter beyond up to 14 days. The immediate type I allergy may range from flush, bronchial obstruction up to allergic shock, whilst delayed-type IV allergy may present with lymphocyte-dependent skin reactions. Rarely, serum sickness disease as a type III allergy is seen. A self-reporting system in the USA with more than 5,000 documented patients calculated a rate of 3% (1.1% acute, 1.7% delayed) in IBD [3]. A pragmatic measure is to administer the antibody in combination with H1 and H2 receptor antagonists as well as glucocorticoids to prevent such problems. Another option is to begin the infusion with infliximab at a low flow rate and to increase it over time. Persisting symptoms despite these measures often lead to a switch to other treatment modalities. Infusion reactions are increased upon episodic treatment. The same happens with the occurrence of antibodies directed against the anti-TNF-α agent (ATI). As such, according to a recent summary, the infusion reaction risk is doubled in the presence of ATIs, but it does not seem to impair efficacy [4].
Infections
Considerable threats were raised at the beginning of the biological era. These included infectious complications due to the ‘shutdown’ of the immune system. Indeed, first reports appeared about infectious adverse events related to anti-TNF-α treatment. An unrecognized infectious complication in IBD may deteriorate, e.g., abscess formation leading to uncontrolled sepsis. Other infectious diseases may even occur in non-IBD patients, tuberculosis for instance, or CMV colitis. The postmarketing data revealed a rate of 0.69% serious infections and at the same time a dramatic increase of activated tuberculosis came apparent [5, 6]. This problem gave rise to the recommendation to screen for tuberculosis, e.g. QuantiFERON Gold Test, and to treat even latent infection prior to administration of the antibody. Since then the reports about tuberculosis have diminished, but other Safety of Anti-TNFs
even untypical manifestations of infectious disease have been encountered, including cytomegalovirus infection, histoplasmosis, Pneumocystis jirovecii pneumonia and aspergillosis, to name some of them. Overall, the rate of infections is increased while on infliximab as well as on other anti-TNF-α antibodies. The TREAT registry describes a doubling of serious infections related to the use of infliximab [7]. Predictors of this adverse event were identified to be age and prednisolone co-administration and this has been replicated in the updated registry with a median follow-up of 5.2 years [3]. Similar findings were observed in rheumatoid arthritis when reviewing the randomized placebo-controlled trials with infliximab and adalimumab. The number needed to harm regarding serious infections was estimated to be 59 (95% CI 39–125) with a pooled odds ratio (OR) of 2.0 (95% CI 1.3–3.1) in favor of anti-TNF treatment [8]. Focusing on adalimumab as the second approved antibody for IBD in Europe, similar infectious adverse events were noted. The latest summary on 71 trials in different indications revealed that Crohn’s disease (CD) bears the highest risk among all indications over time (6.8% compared to 4.1% in rheumatoid arthritis) [9]. Another situation is the postoperative setting in CD and ulcerative colitis (UC). Early data eluded to increased infection rates in CD related to systemic steroids, especially given in higher doses but not to infliximab or immunosuppressives such as azathioprine [10, 11]. Several retrospective series have been combined in three recent meta-analyses. The first two meta-analyses analyzed the diseases separately, thereby omitting retrospective series with a mixed cohort. Regarding UC, no increase in overall, infectious as well as non-infectious complication rates was detected with the use of infliximab [12]. On the contrary, CD complications were raised by the use of infliximab. Local and non-local infections more often occurred while on infliximab and a trend was noted regarding overall and non-infectious complications [13]. The latest meta-analysis with the broadest dataset in IBD confirmed safety of infliximab in the perioperative setting in UC and the signal in CD [14]. Overall complications were raised (OR 2.19, 95% CI 1.69–2.84), the same happened to be with infectious ones (OR 1.93, 95% CI 1.28–2.89), whereas only a trend was observed when focusing on non-infectious problems (OR 1.73, 95% CI 0.94–3.17) in CD. Overall, the likelihood of infectious complications is substantial and is dramatically elevated in case of combined immunosuppression. Steroids are a major issue, but combination with thiopurines and anti-TNF-α treatment exponentially increase this risk [15]. Dig Dis 2013;31:374–378 DOI: 10.1159/000354703
375
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Acute Problems – Infusion Reactions
The most severe adverse event is obviously death. The postmarketing data identified some deaths including fatal tuberculosis [6]. However, now advised precautions prevent the latter infectious complications. Apart from this special infectious problem, the overall mortality seemed to be in excess compared to standard-treated IBD patients when taking studies from referral centers in Europe and the USA into account. The retrospective evaluation from Sweden reported a mortality rate of 1.5% (in addition to a lymphoma rate of 1.5%), the data from the USA are quite similar with 1% of cases definitely related to the use of infliximab [16, 17]. Siegel et al. [18] have evaluated six trials in IBD and reported an increase in mortality based on a decision model. Although infliximab showed a clear benefit over standard treatment in terms of remission induction, they estimated a number needed to kill of 369 due to treatment with infliximab.
Malignancy
With the approval of the anti-TNF-α antibodies, uncertainties arose about cancer development. Reports occurred about lymphoma cases and have been a serious issue since. Especially fatal hepatosplenic lymphoma had been linked to the use of infliximab, but it has to be noted that most cases were related to double immunosuppression with thiopurines [19]. Moreover, we have to acknowledge that in the CESAME cohort, thiopurines alone did serve for an incremental risk of lymphoma [20]. A meta-analysis of randomized placebo-controlled trials evaluated the risk of malignancies in rheumatoid arthritis and reported an increase with the use of anti-TNF treatment. The pooled OR was 3.3 (95% CI 1.2–9.1), accounting for a number needed to harm of 154 (95% CI 91–500) [8]. Summarized data for adalimumab found no increase in lymphoma rates overall, whereas an increase was observed in rheumatoid arthritis [9]. In the same analysis, malignancies tended to be higher in CD treated with adalimumab and this was in part due to an increased number of non-melanoma skin cancers. Of controversy is a large retrospective series from the USA that identified an elevated incidence of melanomas in the IBD population [21]. Thiopurines were found to be related to non-melanoma skin cancer, whereas biological treatment increased the risk for melanoma. This retrospective observation has been integrated in a recent meta-analysis which stated an increased risk for melanoma overall for IBD patients (RR 1.37, 95% CI 1.10–1.70) [22]. However, 376
Dig Dis 2013;31:374–378 DOI: 10.1159/000354703
biologics did not turn out to be a risk factor in this combined analysis, although the above-mentioned largest survey by Singh et al. [22] contributed more than half of all patients. Nonetheless, risk of skin cancer has already been implemented in IBD patient surveillance during immunosuppressive treatment.
Special Situations
Obviously some co-morbidities are risk factors for unfavorable outcomes including cancer and death. The FDA and EMA have acknowledged this on the basis of dedicated trials for other indications. Hence, caution should be exercised when considering TNF blockers for patients with chronic obstructive lung disease or the administration is contraindicated as in advanced chronic heart failure [23, 24]. A similar problem occurred in alcoholic steatohepatitis. Although a beneficial effect had been seen in open-label studies, a randomized controlled study detected an excess mortality [25–27]. Another complication which became apparent was the induction of psoriasis and psoriasiform lesions, although TNF blockers are approved for psoriasis. A recent survey identified 222 cases in the literature describing such adverse events [28]. This complication occurred with all licensed anti-TNF-α antibodies in the treatment IBD. Infliximab resembled two thirds of all cases due to the fact that this biologic was the first to be approved and is the most widely used. The authors concluded that standard topical or systemic standard treatment is the predominant advocated form of therapy and stated that discontinuation is rarely necessary. A concern is viral hepatitis. Whereas hepatitis C seems to be unaffected by TNF blockers, hepatitis B can have a detrimental course [29–31]. Even HBsAg carriers as a form of low replicative hepatitis B may be activated and have to be identified. A treatment with nucleoside or nucleotide analogues is warranted to prevent reactivation and has been shown to be effective. No data are available in case of primary sclerosing cholangitis, autoimmune hepatitis or primary biliary cirrhosis. However, a close follow-up seems mandatory.
Conclusions
TNF blockers are well-accepted IBD treatment options in case of acute steroid treatment failure and when adequate courses of steroids and classical immunosupFellermann
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Mortality
pressives do not work. However, adverse events have to be kept in mind as with other drugs which may discourage early administration. These may be non-severe as for instance infusion reactions but also life-threatening. Serious infections including opportunistic cases are a major issue and increased awareness is vital, especially during combination treatment with other drugs such as steroids. Mortality is increased at least in referral centers reflecting the more severe cases of IBD and is in the range of 1%. The attributed malignancy risk of anti-TNF treatment has to be acknowledged. Lymphomas are rare even in the setting of IBD (contrary to rheumatoid arthritis for instance), but an increase has been documented in several investigations. However, classical immunosuppression puts the patient at risk, too. A new concern is skin cancer,
emphasizing regular dermatological screening. However, infectious complications in IBD overall as well as in the postoperative setting in CD remain the most hazardous problems encountered with biologics. Other drugs, ranging from 5-ASA, glucocorticoids up to classical immunosuppressants, do have their own risks and benefits. ‘Nothing is for free’, this also holds truth for blocking TNF. The clinician has to decide whether the benefits outweigh the risks of treatment.
Disclosure Statement The author has no conflicts of interest to disclose.
References
Safety of Anti-TNFs
8 Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:2275–2285. 9 Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP: Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis 2013;72:517–524. 10 Colombel JF, Loftus EV Jr, Tremaine WJ, Pemberton JH, Wolff BG, Young-Fadok T, Harmsen WS, Schleck CD, Sandborn WJ: Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with infliximab or immunosuppressive therapy. Am J Gastroenterol 2004;99:878–883. 11 Marchal L, D’Haens G, Van Assche G, Vermeire S, Noman M, Ferrante M, Hiele M, Bueno De Mesquita M, D’Hoore A, Penninckx F, Rutgeerts P: The risk of post-operative complications associated with infliximab therapy for Crohn’s disease: a controlled cohort study. Aliment Pharmacol Ther 2004; 19:749–754. 12 Yang Z, Wu Q, Wang F, Wu K, Fan D: Metaanalysis: effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery. Aliment Pharmacol Ther 2012;36:922–928. 13 Kopylov U, Ben-Horin S, Zmora O, Eliakim R, Katz LH: Anti-tumor necrosis factor and postoperative complications in Crohn’s disease: systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2404–2413.
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14 Narula N, Charleton D, Marshall JK: Metaanalysis: peri-operative anti-TNFα treatment and post-operative complications in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;37:1057–1064. 15 Toruner M, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, Colombel JF, Egan LJ: Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008; 134:929–936. 16 Ljung T, Karlén P, Schmidt D, Hellström PM, Lapidus A, Janczewska I, Sjöqvist U, Löfberg R: Infliximab in inflammatory bowel disease: clinical outcome in a population-based cohort from Stockholm County. Gut 2004; 53: 849–853. 17 Colombel JF, Loftus EV Jr, Tremaine WJ, Egan LJ, Harmsen WS, Schleck CD, Zinsmeister AR, Sandborn WJ: The safety profile of infliximab in patients with Crohn’s disease: the Mayo Clinic experience in 500 patients. Gastroenterology 2004;126:19–31. 18 Siegel CA, Hur C, Korzenik JR, Gazelle GS, Sands BE: Risks and benefits of infliximab for the treatment of Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1017–1024. 19 Deepak P, Sifuentes H, Sherid M, Stobaugh D, Sadozai Y, Ehrenpreis ED: T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-α inhibitors: results of the REFURBISH study. Am J Gastroenterol 2013;108:99–105.
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1 Baars JE, Siegel CA, Kuipers EJ, van der Woude CJ: Patient’s perspectives important for early anti-tumor necrosis factor treatment in inflammatory bowel disease. Digestion 2009;79:30–35. 2 Siegel CA, Levy LC, Mackenzie TA, Sands BE: Patient perceptions of the risks and benefits of infliximab for the treatment of inflammatory bowel disease. Inflamm Bowel Dis 2008; 14: 1–6. 3 Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, Langholff W, Londhe A, Sandborn WJ: Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREATTM registry. Am J Gastroenterol 2012; 107:1409–1422. 4 Lee LY, Sanderson JD, Irving PM: Anti-infliximab antibodies in inflammatory bowel disease: prevalence, infusion reactions, immunosuppression and response, a meta-analysis. Eur J Gastroenterol Hepatol 2012; 24: 1078– 1085. 5 Blam ME, Stein RB, Lichtenstein GR: Integrating anti-tumor necrosis factor therapy in inflammatory bowel disease: current and future perspectives. Am J Gastroenterol 2001; 96:1977–1997. 6 Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM: Tuberculosis associated with infliximab, a tumor necrosis factor-αneutralizing agent. N Engl J Med 2001; 345: 1098–1104. 7 Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen DM, Pritchard ML, Sandborn WJ: Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621–30, erratum in Clin Gastroenterol Hepatol 2006;4:931.
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24 Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF Therapy Against Congestive Heart Failure Investigators: Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133–3140. 25 Spahr L, Rubbia-Brandt L, Frossard JL, Giostra E, Rougemont AL, Pugin J, Fischer M, Egger H, Hadengue A: Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized controlled pilot study. J Hepatol 2002;37:448–455. 26 Tilg H, Jalan R, Kaser A, Davies NA, Offner FA, Hodges SJ, Ludwiczek O, Shawcross D, Zoller H, Alisa A, Mookerjee RP, Graziadei I, Datz C, Trauner M, Schuppan D, Obrist P, Vogel W, Williams R: Anti-tumor necrosis factor-α monoclonal antibody therapy in severe alcoholic hepatitis. J Hepatol 2003; 38: 419–425.
27 Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broët P, Emilie D; Foie-Alcool Group of the Association Française pour l’Etude du Foie: A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004;39:1390–1397. 28 Denadai R, Teixeira FV, Steinwurz F, Romiti R, Saad-Hossne R: Induction or exacerbation of psoriatic lesions during anti-TNF-α therapy for inflammatory bowel disease: a systematic literature review based on 222 cases. J Crohns Colitis 2013;7:517–524. 29 Millonig G, Kern M, Ludwiczek O, Nachbaur K, Vogel W: Subfulminant hepatitis B after infliximab in Crohn’s disease: need for HBVscreening? World J Gastroenterol 2006; 12: 974–976. 30 Esteve M, Saro C, González-Huix F, Suarez F, Forné M, Viver JM: Chronic hepatitis B reactivation following infliximab therapy in Crohn’s disease patients: need for primary prophylaxis. Gut 2004;53:1363–1365. 31 Roux CH, Brocq O, Breuil V, Albert C, EullerZiegler L: Safety of anti-TNF-α therapy in rheumatoid arthritis and spondylarthropathies with concurrent B or C chronic hepatitis. Rheumatology (Oxford) 2006; 45: 1294– 1297.
Fellermann
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20 Beaugerie L, Brousse N, Bouvier AM, Colombel JF, Lémann M, Cosnes J, Hébuterne X, Cortot A, Bouhnik Y, Gendre JP, Simon T, Maynadié M, Hermine O, Faivre J, Carrat F; CESAME Study Group: Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009; 374: 1617–1625. 21 Long MD, Martin CF, Pipkin CA, Herfarth HH, Sandler RS, Kappelman MD: Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology 2012;143:390–399. 22 Singh S, Nagpal SJ, Murad MH, Yadav S, Kane SV, Pardi DS, Talwalkar JA, Loftus EV Jr: Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013, E-pub ahead of print. 23 Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, Mahler D, Saadeh C, Siler T, Snell P, Korenblat P, Smith W, Kaye M, Mandel M, Andrews C, Prabhu R, Donohue JF, Watt R, Lo KH, Schlenker-Herceg R, Barnathan ES, Murray J; COPD Investigators: The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175: 926–934.
Adverse Events of Tumor Necrosis Factor Inhibitors Klaus Fellermann Division of Gastroenterology, Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany
Abstract Background/Aims: Adverse events in anti-TNF treatment can be divided into allergic reactions with an acute and delayed onset, infectious complications in relation to the underlying disease, and without. Last but not least, there is the unresolved question of tumor induction and propagation. All of these may account for morbidity and eventually mortality. Methods: Literature-based review to update current knowledge about safety and adverse events of TNF blockers. Results: Major drawbacks are infectious complications with the use of anti-TNF-α antibodies. The risk is increased in inflammatory bowel disease in general and in the perioperative setting of Crohn’s disease patients. The number of tuberculosis cases has decreased since meticulous testing prior to treatment start is mandatory. An excess mortality that has been reported from referral centers is neither documented in randomized controlled trials nor in real-life settings. Regarding malignancies, lymphoma and skin cancer are a concern. The incidence of lymphoma may be raised, but this has also been debated with the use of thiopurines. Skin cancer, especially melanoma, is more common in inflammatory bowel disease and may be associated with the use of biolog-
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0374$38.00/0 E-Mail [email protected] www.karger.com/ddi
ics. Overall, most studies do not address the influence of active inflammation or co-administration of other drugs. Hence, the risk attributable to TNF blockers alone is currently ill-defined. Conclusion: Treatment with anti-TNF-α antibodies is an option with substantial risks. Most problems can be prevented by thorough workup of the patient. © 2013 S. Karger AG, Basel
Introduction
Several years have passed since the approval of the first anti-TNF-α antibody for inflammatory bowel disease (IBD) in 1998. The data basis regarding safety and efficacy is getting more robust now overlooking more than a decade of treatment for diverse diseases. As not all available antibodies have been licensed at the same time, some disparity in the datasets is obvious. In the following, current knowledge of safety issues is presented. In the end the reader has to make his/her own assumptions about the risk-benefit ratio of these biologics and if he/she, the physician as well as the patient are willing to take the risks accompanied with the drug. It has been shown that patients underestimate the burden of anti-TNF-α treatment, pointing to the necessity to properly inform the patient [1, 2].
Prof. Dr. med. Klaus Fellermann Medical Department I, UK-SH Campus Lübeck Ratzeburger Allee 160 DE–23538 Lübeck (Germany) E-Mail klaus.fellermann @ uksh.de
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/16/2015 3:37:15 AM
Key Words Adverse events · Anti-TNF-α · Inflammatory bowel disease · Mortality · Morbidity · Cancer · Infection
Allergy is mostly related to the immunogenicity of the antibody. Due to its chimeric nature, infliximab is more prone to the occurrence of acute as well as delayed infusion reactions. However, all antibodies are proteins with an allergic potential, either administered by the intravenous or subcutaneous route. The infusion reactions can be divided in acute and delayed ones, the former starting immediately up to 4 h, the latter beyond up to 14 days. The immediate type I allergy may range from flush, bronchial obstruction up to allergic shock, whilst delayed-type IV allergy may present with lymphocyte-dependent skin reactions. Rarely, serum sickness disease as a type III allergy is seen. A self-reporting system in the USA with more than 5,000 documented patients calculated a rate of 3% (1.1% acute, 1.7% delayed) in IBD [3]. A pragmatic measure is to administer the antibody in combination with H1 and H2 receptor antagonists as well as glucocorticoids to prevent such problems. Another option is to begin the infusion with infliximab at a low flow rate and to increase it over time. Persisting symptoms despite these measures often lead to a switch to other treatment modalities. Infusion reactions are increased upon episodic treatment. The same happens with the occurrence of antibodies directed against the anti-TNF-α agent (ATI). As such, according to a recent summary, the infusion reaction risk is doubled in the presence of ATIs, but it does not seem to impair efficacy [4].
Infections
Considerable threats were raised at the beginning of the biological era. These included infectious complications due to the ‘shutdown’ of the immune system. Indeed, first reports appeared about infectious adverse events related to anti-TNF-α treatment. An unrecognized infectious complication in IBD may deteriorate, e.g., abscess formation leading to uncontrolled sepsis. Other infectious diseases may even occur in non-IBD patients, tuberculosis for instance, or CMV colitis. The postmarketing data revealed a rate of 0.69% serious infections and at the same time a dramatic increase of activated tuberculosis came apparent [5, 6]. This problem gave rise to the recommendation to screen for tuberculosis, e.g. QuantiFERON Gold Test, and to treat even latent infection prior to administration of the antibody. Since then the reports about tuberculosis have diminished, but other Safety of Anti-TNFs
even untypical manifestations of infectious disease have been encountered, including cytomegalovirus infection, histoplasmosis, Pneumocystis jirovecii pneumonia and aspergillosis, to name some of them. Overall, the rate of infections is increased while on infliximab as well as on other anti-TNF-α antibodies. The TREAT registry describes a doubling of serious infections related to the use of infliximab [7]. Predictors of this adverse event were identified to be age and prednisolone co-administration and this has been replicated in the updated registry with a median follow-up of 5.2 years [3]. Similar findings were observed in rheumatoid arthritis when reviewing the randomized placebo-controlled trials with infliximab and adalimumab. The number needed to harm regarding serious infections was estimated to be 59 (95% CI 39–125) with a pooled odds ratio (OR) of 2.0 (95% CI 1.3–3.1) in favor of anti-TNF treatment [8]. Focusing on adalimumab as the second approved antibody for IBD in Europe, similar infectious adverse events were noted. The latest summary on 71 trials in different indications revealed that Crohn’s disease (CD) bears the highest risk among all indications over time (6.8% compared to 4.1% in rheumatoid arthritis) [9]. Another situation is the postoperative setting in CD and ulcerative colitis (UC). Early data eluded to increased infection rates in CD related to systemic steroids, especially given in higher doses but not to infliximab or immunosuppressives such as azathioprine [10, 11]. Several retrospective series have been combined in three recent meta-analyses. The first two meta-analyses analyzed the diseases separately, thereby omitting retrospective series with a mixed cohort. Regarding UC, no increase in overall, infectious as well as non-infectious complication rates was detected with the use of infliximab [12]. On the contrary, CD complications were raised by the use of infliximab. Local and non-local infections more often occurred while on infliximab and a trend was noted regarding overall and non-infectious complications [13]. The latest meta-analysis with the broadest dataset in IBD confirmed safety of infliximab in the perioperative setting in UC and the signal in CD [14]. Overall complications were raised (OR 2.19, 95% CI 1.69–2.84), the same happened to be with infectious ones (OR 1.93, 95% CI 1.28–2.89), whereas only a trend was observed when focusing on non-infectious problems (OR 1.73, 95% CI 0.94–3.17) in CD. Overall, the likelihood of infectious complications is substantial and is dramatically elevated in case of combined immunosuppression. Steroids are a major issue, but combination with thiopurines and anti-TNF-α treatment exponentially increase this risk [15]. Dig Dis 2013;31:374–378 DOI: 10.1159/000354703
375
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/16/2015 3:37:15 AM
Acute Problems – Infusion Reactions
The most severe adverse event is obviously death. The postmarketing data identified some deaths including fatal tuberculosis [6]. However, now advised precautions prevent the latter infectious complications. Apart from this special infectious problem, the overall mortality seemed to be in excess compared to standard-treated IBD patients when taking studies from referral centers in Europe and the USA into account. The retrospective evaluation from Sweden reported a mortality rate of 1.5% (in addition to a lymphoma rate of 1.5%), the data from the USA are quite similar with 1% of cases definitely related to the use of infliximab [16, 17]. Siegel et al. [18] have evaluated six trials in IBD and reported an increase in mortality based on a decision model. Although infliximab showed a clear benefit over standard treatment in terms of remission induction, they estimated a number needed to kill of 369 due to treatment with infliximab.
Malignancy
With the approval of the anti-TNF-α antibodies, uncertainties arose about cancer development. Reports occurred about lymphoma cases and have been a serious issue since. Especially fatal hepatosplenic lymphoma had been linked to the use of infliximab, but it has to be noted that most cases were related to double immunosuppression with thiopurines [19]. Moreover, we have to acknowledge that in the CESAME cohort, thiopurines alone did serve for an incremental risk of lymphoma [20]. A meta-analysis of randomized placebo-controlled trials evaluated the risk of malignancies in rheumatoid arthritis and reported an increase with the use of anti-TNF treatment. The pooled OR was 3.3 (95% CI 1.2–9.1), accounting for a number needed to harm of 154 (95% CI 91–500) [8]. Summarized data for adalimumab found no increase in lymphoma rates overall, whereas an increase was observed in rheumatoid arthritis [9]. In the same analysis, malignancies tended to be higher in CD treated with adalimumab and this was in part due to an increased number of non-melanoma skin cancers. Of controversy is a large retrospective series from the USA that identified an elevated incidence of melanomas in the IBD population [21]. Thiopurines were found to be related to non-melanoma skin cancer, whereas biological treatment increased the risk for melanoma. This retrospective observation has been integrated in a recent meta-analysis which stated an increased risk for melanoma overall for IBD patients (RR 1.37, 95% CI 1.10–1.70) [22]. However, 376
Dig Dis 2013;31:374–378 DOI: 10.1159/000354703
biologics did not turn out to be a risk factor in this combined analysis, although the above-mentioned largest survey by Singh et al. [22] contributed more than half of all patients. Nonetheless, risk of skin cancer has already been implemented in IBD patient surveillance during immunosuppressive treatment.
Special Situations
Obviously some co-morbidities are risk factors for unfavorable outcomes including cancer and death. The FDA and EMA have acknowledged this on the basis of dedicated trials for other indications. Hence, caution should be exercised when considering TNF blockers for patients with chronic obstructive lung disease or the administration is contraindicated as in advanced chronic heart failure [23, 24]. A similar problem occurred in alcoholic steatohepatitis. Although a beneficial effect had been seen in open-label studies, a randomized controlled study detected an excess mortality [25–27]. Another complication which became apparent was the induction of psoriasis and psoriasiform lesions, although TNF blockers are approved for psoriasis. A recent survey identified 222 cases in the literature describing such adverse events [28]. This complication occurred with all licensed anti-TNF-α antibodies in the treatment IBD. Infliximab resembled two thirds of all cases due to the fact that this biologic was the first to be approved and is the most widely used. The authors concluded that standard topical or systemic standard treatment is the predominant advocated form of therapy and stated that discontinuation is rarely necessary. A concern is viral hepatitis. Whereas hepatitis C seems to be unaffected by TNF blockers, hepatitis B can have a detrimental course [29–31]. Even HBsAg carriers as a form of low replicative hepatitis B may be activated and have to be identified. A treatment with nucleoside or nucleotide analogues is warranted to prevent reactivation and has been shown to be effective. No data are available in case of primary sclerosing cholangitis, autoimmune hepatitis or primary biliary cirrhosis. However, a close follow-up seems mandatory.
Conclusions
TNF blockers are well-accepted IBD treatment options in case of acute steroid treatment failure and when adequate courses of steroids and classical immunosupFellermann
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Mortality
pressives do not work. However, adverse events have to be kept in mind as with other drugs which may discourage early administration. These may be non-severe as for instance infusion reactions but also life-threatening. Serious infections including opportunistic cases are a major issue and increased awareness is vital, especially during combination treatment with other drugs such as steroids. Mortality is increased at least in referral centers reflecting the more severe cases of IBD and is in the range of 1%. The attributed malignancy risk of anti-TNF treatment has to be acknowledged. Lymphomas are rare even in the setting of IBD (contrary to rheumatoid arthritis for instance), but an increase has been documented in several investigations. However, classical immunosuppression puts the patient at risk, too. A new concern is skin cancer,
emphasizing regular dermatological screening. However, infectious complications in IBD overall as well as in the postoperative setting in CD remain the most hazardous problems encountered with biologics. Other drugs, ranging from 5-ASA, glucocorticoids up to classical immunosuppressants, do have their own risks and benefits. ‘Nothing is for free’, this also holds truth for blocking TNF. The clinician has to decide whether the benefits outweigh the risks of treatment.
Disclosure Statement The author has no conflicts of interest to disclose.
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