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Anti-tumor Necrosis Factor Therapy Safety and Toxicity
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The development of anti-tumor necrosis factor-alpha–based therapies for the treatment of Crohn’s disease and ulcerative colitis has been a major advance in the management of these conditions.
Large, randomized controlled trials have demonstrated efficacy in both Crohn’s disease (CD) and ulcerative colitis (UC), leading to the approval for use in both conditions in many countries. Just as important as the demonstration of efficacy these trials, with few exceptions, found the use of anti-tumor necrosis factor-alpha (anti-TNF-α) therapy was not associated with increased risk of adverse effects or toxicity as compared to placebo. Although these clinical trials did not suggest there might be an increased risk of clinically important adverse events or toxicity in the populations studied, the trials were not of sufficient size or duration of follow-up to allow for definitive conclusions regarding the true risk of toxicity and important adverse events related to anti-TNF-a therapy. Medium-sized randomized trials, such as those that were part of the anti-TNF-a development programs, can provide information regarding the incidence of more common adverse events of acute or short-term therapy, but these are not able to provide definitive conclusions regarding less common side effects. In addition, these trials cannot address those adverse events that might occur many years after the start of therapy or those associated with long-term use of anti-TNF-a agents.
Describing those types of adverse events generally requires large post-marketing studies and registries that involve large numbers of patients. In addition, the benefit obtained from these drugs, with respect to the disease-remitting effect and the associated potential improvements in nutritional state, improved patient well-being and decreased rates of disease-associated complications may offset the occurrence of adverse effects that are specifically related to the use of the drug in question.
There are accumulating data regarding complications of anti-TNF-α therapy from large registries and post-marketing surveillance programs with some suggesting that there is an increased risk of serious adverse events occurring with anti-TNF-α therapy, whereas others have suggested there is not any increased incidence relative to what is observed in a comparable population of patients not treated with anti-TNF-α therapy.
This excerpt reviews the current state of knowledge regarding the safety and potential adverse events that have been observed in patients with inflammatory bowel disease (IBD) treated with anti-TNF-α therapy (Table). However, this review will not specifically examine the safety experience of anti-TNF-a agents in patients with other conditions except as directly related to IBD.
Infusion Reactions
Infusion reactions only occur in patients receiving intravenous anti-TNF-α therapy (eg, infliximab [IFX]). The incidence of infusion reactions in randomized controlled trials was between 1% and 4.5% with 5% to 23% of patients experiencing at least one reaction. In open series of IFX-treated patients, infusion reactions have been reported during 6% of infusions and in up to 10% of patients. Infusion reactions usually consist of one or more symptoms of flushing, fever, tachycardia, a sense of chest tightness and shortness of breath. There may be associated hypotension in some cases, but in most instances, there is no hemodynamic instability and no suggestion these reactions are manifestations of anaphylactoid or type I hypersensitivity reactions. However, anaphylactic reactions have been rarely reported. Serious infusion reactions occur in approximately 1% of infusions. Higher rates of acute infusion reactions during IFX infusions may occur in patients who have antibodies against IFX and in those who have stopped therapy and then later received a second course of therapy.
The best strategy for management of infusion reactions is prevention the occurrence before these become a problem. The use of a concomitant antimetabolite immunosuppressive, such as azathioprine, has been shown to reduce the occurrence of acute infusion reactions. Acute infusion reactions can, in some instances, be prevented by giving hydrocortisone 200 mg intravenously just prior to the infusion, but not all studies have been able to confirm this protective effect of glucocorticosteroid pretreatment with respect to the development of a first infusion reaction. In addition, it is not clear whether a potential protective effect of intravenous hydrocortisone extends to patients who are already on an immunomodulator therapy in addition to IFX. For patients who have developed infusion reactions, pretreatment with intravenous hydrocortisone and antihistamines may reduce the incidence of subsequent acute infusion reactions. It also has been the experience of some clinicians that acetaminophen can contribute to the prevention of infusion reactions. Desensitization regimens may effectively prevent reactions in patients who have had anaphylactic or anaphylactoid reactions to IFX and may allow ongoing use of IFX.
Infusion reactions, when they occur, can generally be managed effectively by temporarily stopping the infusion and treating with intravenous antihistamines and oral acetaminophen. Once symptoms have settled, the infusion can be resumed by a gradual upward titration of the infusion rate. This method of upward rate titration also can be used in patients who have had reactions severe enough to require discontinuation of IFX therapy, although some patients may still experience infusion reactions, some of which may be severe. Although acute infusion reactions have been suggested to be related to the rate of infusion, more rapid infusions of IFX, during periods of as short as 30 minutes, can be given without an apparent increase in infusion reactions. When infusion reactions occur despite prophylactic measures, infusion reactions can be avoided by switching to a subcutaneous anti-TNF-α (eg, adalimumab or certolizumab pegol). Overall, infusion reactions are responsible for cessation of IFX in approximately 3% of patients treated, but this can probably be reduced by aggressive prophylactic measures prior to starting therapy or by using the preventive and management measures described above when infusion reactions do occur. What is not entirely known is whether the occurrence of infusion reactions predict a diminished response to IFX by virtue of the fact that the presence of antibodies to IFX have been associated with an increased risk of infusion reactions and may also be associated with diminished efficacy. When IFX is discontinued due to acute infusion reactions, and adalimumab or certolizumab pegol is initiated, there is not an increased risk of adverse reaction to the subcutaneous injection, nor is there any reduction in observed effectiveness.
A second form of infusion reaction is the delayed infusion reaction or serum sickness type of reaction that typically occurs from 2 days to 10 days after the infusion but can occur up to several weeks later. It is characterized by diffuse arthralgias and myalgias, which can often be severe and incapacitating. Although these reactions appear clinically similar to serum sickness in their presentation, there is no end-organ involvement with IFX-related delayed infusion reactions. These infusion reactions typically respond promptly to several days of glucocorticosteroids and may be avoided by a 7-day to 10-day tapering course of glucocorticosteroids started the day prior to an infusion.
Acute reactions, aside from local pain and erythema, are rare with the subcutaneously administered anti-TNF-α agents. The local skin reactions rarely result in the need to discontinue therapy and are not associated with any reduction in efficacy.
Infectious Complications
As the administration of agents that interfere with the action of TNF-α and the cells that produce TNF-α have a dampening effect on certain aspects of cell-mediated immunity, it is not entirely surprising there may be increased incidence of infections caused by microorganisms that are normally controlled or prevented by cell-mediated immunity. The best example of this is the reactivation of latent tuberculosis that was described shortly after IFX was introduced for the treatment of rheumatoid arthritis and CD. Despite the fact that the association between the use of anti-TNF-α therapy and reactivation of latent tuberculosis seems well founded, a subsequent study has shown the rate of tuberculosis was higher in the IBD-patient population compared to that observed in the general population prior to the introduction of anti-TNF-α agents. This suggests the underlying IBD itself, or treatment with steroids or other immunosuppressive medications, predisposes patients to infection with the tuberculous bacillus.
Recognition of reactivation of latent tuberculosis as a potential complication has led to recommendations for pretreatment screening and introduction of prophylaxis or avoidance of anti-TNF-α therapy for at-risk individuals, with subsequent reduction in rates of tuberculosis. It is generally recommended that all patients who are being considered for anti-TNF-α therapy be screened for latent tuberculosis according to local guidelines and adjusted according to the patient’s individual demographic and clinical situation. Patients who are found to have, or are strongly suspected of having, latent tuberculosis should generally receive antituberculous prophylaxis prior to initiating anti-TNF-α therapy. The optimal duration of antituberculous therapy prior to starting anti-TNF-α therapy is not known. The decision in individual patients requires a balance between the risk of reactivation of tuberculosis if anti-TNF-α therapy is started too early in the course of prophylactic therapy versus the risk of worsening or complicated IBD if introduction of anti-TNF-α therapy is delayed too long. Antituberculous prophylaxis is not universally effective and infection can occur despite adequate prophylaxis.
Although tuberculosis provided an important example of the potential risk of the immune suppression produced by blocking the action of TNF-α or by eliminating the cells producing TNF-α, the overall infection rate does not appear to be increased in patients treated with IFX or the other anti-TNF-α antibodies based upon a meta-analysis of randomized controlled trials. This was confirmed by a large postmarketing registry involving 3179 patients who were treated with IFX and were compared to a similar number of patients with CD who had not received IFX or other anti-TNF-α therapies. Data from a large population-based administrative health care utilization database of 10,662 IBD patients found no statistically significant increased risk of serious bacterial infection in patients treated with IFX as compared with other immunosuppressive agents. Despite the absence of proof of an association between anti-TNF-α therapy and serious bacterial infection, there are a number of open or retrospective series that have reported rates of serious infection as being between 4% and 15% of patients. Although the lack of an appropriate reference population limits the inferences that can be made from these data, these study results do argue for increased vigilance for bacterial infections in patients with IBD that is severe enough to require anti-TNF-α therapy.
Although there is no evidence from prospective controlled trials that serious bacterial infections are increased in IBD patients on anti-TNF-α therapy, there are numerous reports of opportunistic infections occurring in these patients. The occurrence of opportunistic infections is likely an unusual event, but their detection requires careful clinical monitoring and a high index of suspicion. Although opportunistic infections appear to occur at a low level, some specific infectious agents appear to have been reported with higher than expected frequency. The FDA Adverse Event Reporting System registered a total of 84 cases of Pneumocystis jiroveci (carinii) pneumonia in patients with CD treated with IFX during a 5-year period, up to 2003. This has led at least one organization to recommend cotrimoxazole prophylaxis against Pneumocystis for patients receiving anti-TNF-α therapy along with 2 or other immunosuppressive medications.
The specific role of the anti-TNF-α therapy in the pathogenesis of serious bacterial infections and opportunistic infections that occur in patients receiving these agents is not completely known. In many instances, patients who develop opportunistic infections are also receiving treatment with immunosuppressives or steroids, and as such, the role of an anti-TNF-α agent in serious infections relative to that of the other pharmacotherapies is not clear. A retrospective case-control study from a tertiary care center has suggested that steroids, immunosuppressives, and anti-TNF-α agents each individually increase risk, but that the combination of any 2 or 3 further increases the risk. However, the increased risk of infection with dual therapy incorporating an anti-TNF-α agent and an antimetabolite immunosuppressive drug has not been substantiated by prospective randomized controlled trials.
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Excerpted From
Regueiro MD, Swoger JM, eds. Clinical Challenges and Complications of IBD (pp 303-326) © 2013 SLACK Incorporated.