Adverse effects of biologics used for treating IBD

Best Practice & Research Clinical Gastroenterology 24 (2010) 167–182

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Best Practice & Research Clinical Gastroenterology

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Adverse effects of biologics used for treating IBD Andreas Stallmach, MD, Professor *, Stefan Hagel, MD, Resident Physicians, Tony Bruns, MD, Resident Physicians Division of Gastroenterology, Hepatology and Infectious Disease, Department of Internal Medicine II, Friedrich Schiller University of Jena, Erlanger Allee 101, 07740 Jena, Germany

Keywords: Tumor necrosis factor-alpha Inflammatory bowel diseases Infections Neoplasms Safety Risk factors Immunosuppressive agents

In the last decade, biologic agents, in particular anti-TNF agents such as infliximab, adalimumab, and certolizumab have substantially extended the therapeutic armamentarium of inflammatory bowel disease (IBD). Additional approaches include biologicals, such as natalizumab, that block leucocyte adhesion; those that target cytokines, such as interleukin-12/23 antibodies; or those that inhibit T-cell signaling, such as interleukin-6 receptor antibodies. However, these drugs have a number of contraindications and side effects, especially when used in combination with classical immunosuppressive agents or corticosteroids. Areas of concern include opportunistic infections, malignancies, and miscellaneous complications such as injection/infusion reactions and autoimmunity and contraindications, such as heart failure and acute infectious diseases. In this review, the indications of biologicals in IBD treatment are briefly reported, and the potential disadvantages of a more active therapeutic approach in IBD are discussed. We have learned in the last decade that anti-TNF-a therapy is an effective and relatively safe treatment option for selected patients that changes the natural course of severe IBD. However, despite these changed therapeutic paradigms and goals in IBD, clinicians should be aware that the powerful immunosuppressive capacity of biologicals necessitates a rigorous long-term safety follow-up. Ó 2010 Elsevier Ltd. All rights reserved.

Biological therapies for inflammatory bowel diseases Although the causes of IBD are unknown, defects in innate and adaptive immune pathways have been identified, and biological therapies that target key molecules have been designed. The * Corresponding author. Tel.: þ49 3641 9324221; fax: þ49 3641 9324222. E-mail address: [email protected] (A. Stallmach). 1521-6918/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.01.002

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fundamentals of biological treatment strategies involve neutralization of pro-inflammatory cytokines, use of anti-inflammatory cytokines, and inhibition of neutrophil adhesion or T-cell signaling. Based on large randomized clinical trials, anti-TNF-a agents, such as infliximab, adalimumab, or certolizumab, have substantially extended the therapeutic armamentarium in IBD. Other potential treatment options include monoclonal antibodies to cytokines IL-12/23p40 (ustekinumab and ABT-874) and IL-6 (tocilizumab), antibodies to T-cell surface receptors such as CD25 (basiliximab), fusion proteins that block co-stimulatory receptor function such as CD80/86 (abatacept), antibodies to block chemokines or adhesion molecules such as natalizumab, and mucosal delivery of recombinant human regulatory cytokines like IL-10. In our view, there are three important points concerning biological therapies in IBD: Firstly, for the majority of IBD patients, standard treatment with 5-ASA, budesonide, or systemic steroids is rather effective for the induction of remission. There is obviously a bias of opinion leaders regarding the severity of IBD and the need for more active treatments. With respect to population-based data, fewer than 50% of all patients with IBD need steroids during their lifetime [1,2]. However, there is a group of patients that cannot be sufficiently treated with the standard options, which include classical immunosuppressive agents such as azathioprine or methotrexate (MTX). Biological therapy in these patients is a promising option to reduce the need for corticosteroids and immunosuppressive agents. Moreover, this treatment shortens hospital stays, prevents surgical procedures, extends the remission period, and improves the quality of life [3,4]. Secondly, the emergence of effective biological therapies has led to a clinical debate about ‘step-up’ versus ‘top-down’ strategies. ‘Step-up’ refers to the classic therapeutic approach, namely the progressive intensification of treatment as disease severity increases. ‘Top-down’ refers to the early introduction of intensive therapies, including biological agents in all IBD patients with the aim of avoiding complications and improving quality of life, starting from the assumption that these drugs may interfere with the natural progression of the disease. Another important aspect of the debate, our third point, is the question of whether immunosuppressive agents such as azathioprine or MTX must be added to biological treatments of IBD. Although this combination can increase therapeutic efficacy and help prevent immunogenicity, concerns about the risk of adverse effects, particularly infections and malignancy, have been raised. Incontrovertible data about the serious adverse events and deaths associated with biologic therapies do exist. Due to the relatively low incidence of these events, randomized controlled trials may be underpowered to detect specific risks. Larger populations for analysis are available from registries and post-marketing surveillance; however, registry data are biased by non-random treatment allocation and post-marketing data lack full reporting, exposure estimates, and a control group. Given the problems with these single sources of information, data pooling techniques play an important role in determining the relative safety of treatments. As each of the individual biological trials in IBD has been too small to allow for a meaningful quantification of the relative occurrence of cancer, meta-analytic approaches aim to estimate cancer risk across trials. To complicate matters further, in a typical trial, there is a 2-3:1 ratio between the number of patients treated with a biologic and the finite number receiving the comparator treatment. As a result, statistical precision may be critically dependent on individual cases of cancer in the comparator, and an increased risk may be more easily detected than a decreased risk. Infectious complications One key safety concern with biologic immunosuppressive agents is the potential for serious infections, defined as fatal, life-threatening, or causing prolonged hospitalization, and this concern includes opportunistic infections. Opportunistic infections (OIs) are infections caused by organisms that take advantage of a weakened immune system and cause disease when they ordinarily would cause mild or no disease in an immunocompetent host. When they occur, OIs are often associated with significant morbidity and mortality, as they are frequently serious and hard to treat effectively [5]. There is consensus among experts that IBD patients should not be considered systematically immunocompromised in the absence of immunosuppressant therapy or malnutrition, despite evidence for a defect in mucosal innate immunity [6]. Infections are not increased in the overall

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population of IBD patients. In general, patients with IBD become immunocompromised as a result of treatment. However, the extent to which biologic agents, alone or in combination with immunosuppressive medications, increase the risk of serious infections in patients with IBD remains controversial. Due to low infection rates, large cohort studies are needed to determine their precise incidence and to establish the excess risk associated with the use of a specific medication, particularly while administering older traditional therapies which have been less scrutinized and also carry their own risks [7]. Granulomatous infections such as tuberculosis have received the most attention, while case reports and post-approval databases suggest increased rates of infections of other pathogens (virus, intracellular bacteria, fungi, and parasites), which have been regularly stated to be a cause of death in this population [7,8]. In an early retrospective study of 500 patients treated with infliximab for IBD in the Mayo Clinic [9], the most frequent serious adverse event was infection (8.2%), leading to four deaths. This observation agrees with the results of an analysis of 620 patient-years of follow-up by Lees et al. [10], who reported a 9.9% incidence of serious infections in a cohort of IBD patients treated with anti-TNF-a agents. However, a majority of infectious events occurred in the presence of concomitant immunosuppression, while in contrast to other reports [11,12], an increased risk of infection for patients on thiopurines or corticosteroids was not observed [10]. In a Swedish population-based study of 217 IBD patients, 8.3% of patients acquired a serious infection, and two patients died from sepsis during infliximab therapy [13]. In contrast, the 7th Periodic Safety Update Report (PSUR 7) indicated that the rate of serious infections in patients treated with infliximab was not higher than in patients treated with placebo (6.2% vs. 6.8%). Further, Schneeweiss et al. [14] reported identical rates of serious bacterial infections in patients treated with infliximab (8.9 per 1000 patient-years, 95% CI 3.2–19.3) and in patients treated with other immunosuppressive agents, including corticosteroids, thiopurines, and methotrexate (6.8 per 1000 patient-years, 95% CI 4.5–9.9) in a population-based cohort of 10,662 IBD patients (RR ¼ 1.1, 95% CI 0.42–2.74). Furthermore, based on a few events, initiators of infliximab who were already treated by an immunosuppressive agent were not at a higher risk of serious bacterial infections compared with initiators of immunosuppressants who also used at least one other immunosuppressive drug (RR ¼ 0.7, 95% CI 0.22–3.28) [14]. This finding agrees with the observation of Fidder et al [15] who reviewed the medical records of 743 infliximab-treated and 666 infliximab-naı¨ve IBD patients over a median follow-up of 58 months and 144 months, respectively. No difference in infection rates was observed between the two groups; however, concomitant therapy with steroids was the only independent risk factor for infections in infliximab-treated patients with a 2.7-fold increased risk of infection (95% CI 1.18–6.12) [15]. This observation was confirmed in the prospective, observational, multicentre TREAT registry of 6290 patients with Crohn’s disease (CD) [11]. The rate of serious infections in 3334 patients treated with infliximab (1.19 per 100 patient-years within three months of an IFX infusion and 0.67 per 100 patient-years not within three months of an IFX infusion) was significantly higher than in infliximab-naı¨ve patients (RR ¼ 1.77, 95% CI 1.27–2.46). However, after adjusting for other variables, infliximab did not remain a significant predictor of serious infections (HR ¼ 1.28, 95% CI 0.87–1.90), whereas the increased infection rate in the anti-TNF-a treated patients was most likely a result of concurrent steroid use (HR ¼ 2.04) and narcotic analgesic use (HR ¼ 2.17) [11]. Additional information on whether biologics contribute to infection is available from the studies of anti-TNF-a treatment of rheumatoid arthritis (RA), albeit there are also conflicting data. For example, in a meta-analysis by Bongartz et al. [16], including randomized controlled trials (RCTs) of infliximab and adalimumab use in RA, a pooled odds ratio of 2.0 (95% CI 1.3–3.1) for serious infections was calculated. In contrast, two recent observational studies [17,18] contradict these findings, reporting no increased risk of infection compared to the cohort treated with disease modifying antirheumatic drugs (DMARDs). However, data from patients with RA must be regarded with the understanding that these patients already have an increased risk of infection as a result of altered immune regulation, debility, and co-morbidity [19]. However, in a recently conducted comprehensive safety review of adalimumab in all six of its approved disease indications, Burmester et al. [20] reported the largest rates of serious infections in RA and CD clinical trials with 4.6 and 5.2 events per 100 patient-years, respectively, hence demonstrating an even higher incidence rate in patients with CD.

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Tuberculosis Biologic plausibility exists for an association of TNF-a blockade and tuberculosis (TB) because TNFa plays an imminent role in defence against mycobacteria and in the pathology of the infection [21]. TNF gene-targeted mice, for example, developed fatal disseminated TB with compromised granuloma formation when they were infected with Mycobacterium tuberculosis [22]. The impairment of granuloma formation is the likely mechanism of extra-pulmonary disease and the severe clinical course seen with TNF-a inhibition [23,24]. Before the approval of infliximab in 1998 there was only a single case of TB during the clinical trials for infliximab in RA patients [25]. However, after its use in clinical practise, the post-marketing surveillance demonstrated a strong relationship between treatment with anti-TNF-a agents and the development of TB [24,26]. The cumulative exposure and reporting rates for TB indicate that before widespread screening for latent tuberculosis infection (LTBI) was initiated, it was the most common OI related to anti-TNF-a therapy. Several studies indicated a 5- to 30-fold increased risk of TB infection compared to the general population [26]. Analyzing data from different registries of patients treated with biologicals showed an incidence rate of 0.9–1.5 TB infections per 1000 person-years [17,26]. TB typically presents after 11–12 weeks of treatment with infliximab and after 30 weeks of treatment with adalimumab. Importantly, the symptoms of fever, weight loss, and night sweats are all TNF-mediated and can, therefore, be masked by anti-TNF-a agents and lead to atypical presentations. Furthermore, TB enteritis can mimic CD, and all efforts should be made to rule out TB before initiating TNF-a inhibitors. Recently, Wallis et al. [27] showed in a mathematical model that the rate of reactivation of LTBI by infliximab was more than 20% per month of treatment, causing 75% of LTBI in the first year of therapy. However, the analysis also revealed that both drugs caused a high proportion of new infections to progress directly to active disease. In this model, the high monthly reactivation rate associated with infliximab therapy rapidly converted latent TB infections to active TB, leaving only 6% of infections in the latent state at one year, at which point, the progression of new infection became the predominant cause of TB [27]. Strategies to reduce the risk of TB due to TNF-a blockade emphasize the detection and treatment of LTBI. The effectiveness of this strategy has been documented by the Spanish BIOBADASER registry [28], which showed a 74% decline in TB infections. The current practise includes screening with the tuberculin skin test (TST) and chest radiography to identify regional scarring and hilar lymphadenopathy before anti-TNF-alpha therapy. However, the specificity of the TST with purified protein derivate (PPD) is reduced by antigens shared by non-tuberculous mycobacteria, including Mycobacterium bovis bacillus Calmette-Guerin (BCG) used for previous vaccination. Furthermore, TST may be negative in patients on immunosuppressants, and the test cannot be adequately interpreted if medication is not discontinued for several weeks prior to testing [29,30]. Indeed, of the 69 TB cases in the RATIO study [26], 45 had undergone TST screening, and 30 patients were found to be negative. In contrast, T-cell-based interferon-gamma release assays (IGRA), which use antigens that are highly specific for TB, are superior to the TST for LTBI screening [30,31]. The Centers for Disease Control and Prevention (CDC), therefore, has clearly recommended that IGRA testing should replace the TST in patients being screened for TB before initiating anti-TNF-a therapy [32]. However, it must be mentioned that in light of the lack of a gold standard test for LTBI screening in immunocompromised patients, it is difficult to ascertain the true sensitivity and specificity for IGRA, and false negative results might be possible and could mediate a false sense of security. Therefore, interferon-gamma assays do not replace a careful clinical workup and observation of our patients before and during anti-TNF-a therapy. Recent guidelines suggest that patients diagnosed with LTBI should be treated with a complete therapeutic regimen for LTBI. When there is LTBI and active IBD, anti-TNF-a therapy should ideally be delayed for at least three weeks after starting chemotherapy. In cases of active TB, treatment should ideally be completed before starting biological therapy, although no prospective or controlled data are available on the ideal timing of anti-TNF-a therapy once TB treatment has begun [6]. There are also no data regarding the optimal management of patients who develop TB due to TNF blockade. The ECCO guidelines [6] recommend halting anti-TNF-a therapy and resuming it after two months, if needed. However, recent case reports have described patients with active TB infection who developed a paradoxical reaction after stopping anti-TNF-a therapy due to recovery of TNF-dependent inflammation

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with marked worsening despite microbiologic improvement. After resuming anti-TNF-a treatment, the clinical conditions of these patients improved [33,34]. With an estimated one-third of the world’s population having LTBI and an increasing use of anti-TNF-a therapy in high prevalence countries, the reduction of reactivation and progression of TB is of considerable public health importance. Furthermore, considering the observation of the Food and Drug Administration (FDA) that 91% of spontaneous reports of TB are from countries with low TB incidence, the magnitude of the problem is most likely underestimated [24]. Fungal and parasitic infections In addition to TB, several endemic and opportunistic infections associated with anti-TNF-a therapy have been reported. Cases of local and systemic candidiasis, atypical bacterial infections, aspergillosis, coccidioidomycosis, legionellosis, cryptococcal infections, nocardiosis, toxoplasmosis, Pneumocystis jiroveci pneumonia, disseminated sporotrichosis, and Histoplasma capsulatum infections have been observed [19,35]. In many of these infections, TNF-a plays a prominent role in the host defence against the causative organisms. For example, a murine model has shown that TNF-a is produced in response to challenge with H. capsulatum, and treatment of mice with anti-TNF-a antibody results in a fatal disseminated histoplasmosis [36]. Furthermore, TNF-a plays an important role in activating macrophages and enhancing their anti-bacterial activity against Listeria monocytogenes [37]. Several reports of patients who developed listeriosis under treatment with TNF-a therapy have been reported. One study found a relative risk of Legionella pneumophila pneumonia in anti-TNF-a-treated patients of 16.5–21, compared with the overall population [26]. However, all of the 10 reported patients were on concomitant therapy with corticosteroids and/or methotrexate; therefore, conclusions about the influence of anti-TNF-a therapy on the risk of legionellosis are difficult to make. The mechanisms by which TNF-a inhibition increases susceptibility to invasive fungal infections include inhibition of interferon-g production, reduction of pattern-recognition receptor expression, and leucocyte apoptosis. A comprehensive review about the complication of fungal infections of TNFa blockade therapy was recently conducted by Tsiodras et al [38] who identified 281 cases with fungal infections associated with TNF-a inhibition up to June 1st, 2007. However, as in other studies concerning infectious complications in anti-TNF-a therapy, a majority of patients were treated with concomitant immunosuppressive medication. For instance, 98% of patients were treated with systemic corticosteroids, which also increases the risk for fungal infections [5]. The most prevalent fungal infections were histoplasmosis (30%), candidiasis (23%), and aspergillosis (23%). Pneumonia was the most common pattern of infection. Of the 90 out of 281 cases (32%) for which outcome information was available, a high mortality of 32% (n ¼ 29) was recorded [38]. Viruses Thiopurine metabolites leading to T-lymphocyte apoptosis may predispose one to infection by viruses such as cytomegalovirus (CMV), varicella zoster virus (VZV), or Epstein–Barr virus (EBV) [7]. In the 18th Periodic Safety Update Report (PSUR 18) on infliximab, herpetic infections were one of the leading infectious complications (23%) over 10 years. There have been concerns about the risk of CMV reactivation with the use of biologic agents. In a prospective evaluation of 15 patients with RA receiving infliximab, no cases of CMV reactivation were found [39]. In contrast, Helbling and colleagues [40] described a patient who developed a CMV infection after receiving a single dose of infliximab while on concomitant treatment with corticosteroids and azathioprine. With respect to EBV infection, Reijasse et al [41]. did not find any difference in EBV serial viral loads between EBV-positive CD patients receiving infliximab and EBV-positive healthy controls over an 18-month period. Regarding VZV, several cases of patients who developed shingles and primary VZV infection under treatment with infliximab have been reported [42], and primary VZV infection may present with atypical features in patients on anti-TNF therapy. Furthermore, reactivation of herpes zoster was recently stated to be the most common viral problem associated with anti-TNF-a treatment and may be particularly severe [43]. Therefore, screening for VZV antibodies prior to initiation of anti-TNF-a therapy and prophylactic vaccination in patients who do not exhibit immunity is recommended [6].

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The role of TNF-a in the regulation and replication of hepatitis C virus (HCV) is unclear. Case series suggest that anti-TNF-a therapy has no adverse effects or might even improve complications of chronic hepatitis C [44]. The effect of anti-TNF-a therapy on the course of hepatitis B infection in IBD patients has not been studied prospectively, but cases of symptomatic and severe flares in HbsAg-positive IBD patients receiving infliximab have been reported [42]. Therefore, the ECCO guidelines [6] recommend preemptive therapy with anti-viral agents, regardless of the degree of viremia, in HBsAg-positive individuals before immunomodulator treatment in order to avoid acute flares. Furthermore, testing prior to therapy to rule out hepatitis B virus (HBV) infection and vaccination in all sero-negative patients with IBD is mandatory. TNF-a has been implicated to contribute to HIV replication and the course of infection [45]. Studies on the effect of anti-TNF-a therapy on HIV infection have indicated that there is no worsening of infection and, therefore, anti-TNF-a therapy may be given to IBD patients with coexisting HIV infection. However, immunosuppressive therapy may increase the severity of HIV-related infections and, therefore, HIV testing is recommend prior to therapy [6]. Special concerns exist for progressive multifocal leukoencephalopathy (PML), a rare but usually fatal opportunistic brain infection caused by reactivation of latent JC (polyoma) viral infection under treatment with natalizumab [46]. Reactivation of the JC virus in the brain results in demyelination, giant astrocytosis, and destruction of glial cells, and it is clearly associated with profound immune suppression. After suspension of commercial and investigational use for CD and multiple sclerosis in 2005, natalizumab therapy was subsequently resumed for both indications; however, it is only available through restricted distribution programs in the USA [6]. The current estimated risk for PML in patients treated with natalizumab is 1/1000 [46], and the lack of adequate therapeutic options calls for reliable screening strategies. However, whether or not JC viral load assessments in blood, urine or cerebrospinal fluid can predict the risk of PML is debated [6,47]. Therefore, patients on anti-a4-integrin therapy should be closely monitored for neurological symptoms such as lethargy or personality change, which should prompt further diagnostics with contrast-enhanced cranial MRI and lumbar puncture. In conclusion, despite 10 years of experience, the extent to which biologic agents increase the risk of serious infections by bacterial, fungal, parasitic, or viral pathogens is still a matter of debate. Upon summarizing the endpoints and statistical models used in these very heterogeneous studies, we conclude that treatment with biological agents alone increases the risk of serious infections to the same degree as classical immunosuppressive agents or repeated corticosteroid use. Additionally, we conclude that treatment with biological agents increases the risk of granulomatous infections, especially TB. With the introduction of biologic therapies for IBD, most leading clinical investigators have advocated the combination of immunosuppressive therapy with biologicals, primarily to reduce the induction of anti-biological antibodies and improve the outcome of patients. Very recently, the double-blind placebo-controlled SONIC [48] trial demonstrated that infliximab in combination with azathioprine induced remission and mucosal healing in a cohort of patients with early CD more effectively. However, large randomized clinical trials with the three different anti-TNF-antibodies and natalizumab have failed to demonstrate the clinical superiority of combination therapy. Therefore, the benefits and risks of combination therapy are a primary focus in terms of both efficacy and side effects. In this context, a casecontrol study by Toruner et al [12] is of fundamental importance. They recently demonstrated that combinations of immunosuppressant therapies in IBD patients are associated with an incremental increase in the relative risk of opportunistic infections. Specifically, patients experienced a three-fold increased risk for OIs (OR 2.9, 95% CI 1.5–5.3) if corticosteroids, azathioprine (AZA)/6-mercaptopurine (6MP) or infliximab were used alone, and the risk increased substantially if two or more drugs were used concomitantly (OR 14.5, 95% CI 4.9–43) [12]. However, a possible bias in these results may be that patients with more advanced disease, and, therefore, with a possibly increased risk of developing infectious complications due to their underlying disease, are more likely to be on combination therapy. Further, of 605 patients who were exposed to immunosuppressive medications, a significantly larger percentage of patients exposed to combination immunosuppressive therapy developed non-opportunistic infectious complications (7%) compared to those on monotherapy (3%; p ¼ 0.02) [49] (see also Fig. 1). The majority of patients with fungal infections were also on concomitant immunosuppressive therapy [38], and the TREAT registry showed that the increased risk of infections during anti-TNF-

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Fig. 1. Risk of opportunistic and non-opportunistic infections among patients treated for IBD with corticosteroids, immunosuppressants, and biologicals.

a therapy was associated with the use of corticosteroids [11]. In summary, concomitant immunosuppression is an important risk factor for increased infection rates during biological therapy. Therefore, physicians treating patients with anti-TNF-a therapy should be aware of the possibility of the development of serious infections, particularly in the context of concomitant immunosuppressive medication in severely ill patients. Anti-TNF-a agents and other immunosuppressive medications may mask the symptoms of serious infections; therefore, patients on anti-TNF-a therapy should be monitored for the early signs and symptoms of infection with aggressive evaluation and management. Before initiating therapy, patients must be evaluated for the presence of infection; screening for LTBI, hepatitis B and C, HIV, and serum and urine screening studies for endemic mycoses are recommended. Furthermore, verifying patient vaccination status and regular vaccination for influenza and pneumococcal disease should be performed. Malignancies Since the introduction of anti-TNF-a therapy, there have been concerns about an increase in malignancies because of the role of TNF in NK cell-mediated and CD8þ T-cell-mediated tumour cell elimination. In August 2009, the FDA now requires stronger warnings about the possible occurrence of lymphoma, leukemia, and solid cancers in patients receiving anti-TNF-a therapy on the basis of 48 cases of malignancies in children and adolescents and 147 post-marketing reports of leukemia in all patients, including adults [50]. Lymphoma Patients receiving infliximab in controlled clinical trials for all indications (CD, ulcerative colitis, RA, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis) developed more lymphomas (5 cases in

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5707 patients, 100 in 100,000 patient-years) than patients in the respective control groups (0 cases per 1600 patients) [51]. This finding represents an approximately five-fold increase in the age-adjusted incidence rate for non-Hodgkin’s lymphoma in the general population (19.5 in 100,000 persons per year), according to the U.S. Surveillance, Epidemiology, and End Results (SEER) cancer registry [62]. Because these controlled trials had a median follow-up of 1.0 years, the effects of long-term therapy were not considered. It is important to note that the risk of lymphoma is very likely to be influenced by the underlying disease, its activity and duration, and immunosuppressant co-medication of the selected individuals. Patients who suffer from RA have a markedly increased lymphoma risk due to the underlying disease, with a standardized incidence ratio (SIR) of 2.0 (95% CI 1.8–2.2) based on Swedish registry data [52]. RA-associated malignant lymphomas occur after 20 years mean duration of disease and are mostly diffuse large B cell lymphomas and are EBV-negative [53]. A case-control study of 378 cases identified disease activity, elevated erythrocyte sedimentation rate, and severe irreversible joint damage, but not DMARD therapy, as predisposing factors for lymphoma development [53]. Large population-based lymphoma risk assessment studies [54,55] indicate that the disease-related risk of lymphoma is not further increased by anti-TNF-a therapy in RA. Askling et al [54] reported 26 malignant lymphomas among 6604 RA patients treated with anti-TNF-a therapy during a follow-up of 26,981 patient-years (96 in 100,000 patient-years). Although lymphoma incidence in RA patients treated with anti-TNF-a agents was increased compared to the general population (RR ¼ 2.7, 95% CI 1.8–4.1), it was identical to the risk in anti-TNF-a-naı¨ve RA patients (RR ¼ 1.4, 95% CI 0.8–2.1) [54]. A cohort study by Wolfe and Michaud [55] identified 43 lymphomas in 10,815 anti-TNF-a–treated patients during a median follow-up of 3.4 years. The risk of lymphoma was identical in anti-TNFa treated and anti-TNF-a-naı¨ve patients (OR ¼ 0.9, 95% CI 0.5–1.5). The combination of anti-TNFa agents with methotrexate did not increase the risk of lymphoma compared to MTX alone (OR ¼ 1.1, 95% CI 0.6–2.0), and there was no difference of lymphoma incidence in individuals treated with MTX compared to other DMARDs (OR ¼ 1.3, 95% CI 0.6–2.7) [55]. In contrast to RA, studies have failed to demonstrate an overall increased risk of malignant lymphoma in patients with IBD. The largest population-based cohort study [56] of anti-TNF-a-naı¨ve patients with IBD that assembled data from the Uppsala cohort, the Stockholm County cohorts, the Stockholm pancolitis register, and the Swedish inpatient register, followed more than 47,000 patients with IBD for up to 40 years. In CD, the risk of malignant lymphoma was marginally elevated due to 65 cases, resulting in a SIR of 1.3 (95% CI 1.0–1.6, n ¼ 20,120). The lymphoma risk in CD was increased for the subgroup of male patients (SIR ¼ 1.5) within the first five years of follow-up (SIR ¼ 1.6) without any significant variation in risk with disease severity, but results were limited due to less available data on severity (n ¼ 3587); whereas the lymphoma risk in patients with ulcerative colitis (UC) was similar to the general population (SIR ¼ 1.0, 95% CI 0.8–1.3, n ¼ 27,559) [56]. A previously published populationbased study [57] on 16,996 patients with IBD registered in the UK General Practice Research Database found no significant elevation in lymphoma risk in UC (SIR ¼ 1.2, 95% CI 0.6–2.2) and in CD (SIR ¼ 1.4, 95% CI 0.5–3.4) over an average follow-up of four years. The number of patients that have received immunosuppressants within five years is currently between 22% in prospective unselected cohorts [58] and 56% in tertiary centres [59]. A meta-analysis of six cohort studies by Kandiel et al [60] demonstrated a markedly increased risk for lymphoma in IBD patients receiving thiopurines compared to the general population (SIR ¼ 4.2, 95% CI 2.1–7.5). After the exclusion of two studies causing significant heterogeneity, the risk for lymphoma remained significantly elevated (SIR 2.9–4.6). However, this increased risk may be due to immunosuppressant medication, underlying disease activity, or both. Because approximately two-thirds of anti-TNF-a-treated patients receive concomitant immunosuppressant medication in clinical studies [61], the safety evaluation of TNF-a antagonists remains challenging. A recent meta-analysis by Siegel and co-workers[61] analysed 26 studies (9 RCTs, 14 case series, three cohort studies) involving 8905 patients and 21,178 patient-years of follow-up to estimate the risk of non-Hodgkin’s lymphoma (NHL) in patients with CD receiving anti-TNF-a therapy. Thirteen cases of NHL were observed during follow-up, yielding 61 lymphomas in 100,000 patient-years. The risk of NHL was more than three-fold increased in individuals receiving biological therapy for IBD (SIR ¼ 3.2, 95% CI 1.5–6.9) compared to the general population, but was identical to the NHL incidence

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in CD patients receiving immunosuppressants, as estimated by the data from Kandiel et al [60]. (SIR ¼ 1.7, 95% CI 0.5–7.1) [61]. However, the results of this meta-analysis were biased by a populationbased case series from Stockholm County that reported three cases of lymphoma in a CD cohort of 191 patients (1485 in 100,000 patient-years) [13]. Both the subgroup analysis of nine RCTs on infliximab, adalimumab, and certolizumab pegol in IBD (2 cases in 3860 patient-years) and the extensive TREAT registry data on infliximab in CD (6 cases per 13,126 patient-years) failed to demonstrate an increased risk of NHL compared to SEER cancer registry data [62] (SIR ¼ 2.6, 95% CI 0.2–35.7) [61] and to infliximab-naı¨ve CD patients (RR ¼ 0.8, 95% CI ¼ 0.22–2.99) [63], respectively. Until 2008, 18 cases of hepatosplenic T-cell lymphoma (HSTCL) in patients receiving anti-TNFa therapy for IBD have been reported [64,65]. All patients received infliximab in combination with azathioprine or 6-mercaptopurine. Since only 200 cases of HSTCL have been reported, its occurrence is presumably associated with infliximab use in young patients with IBD. Interestingly, 10 additional cases of HSTCL have been reported with thiopurine use in IBD without concomitant anti-TNF-a treatment [64]. Currently, it is not known whether infliximab, thiopurines, or the combination of both have a primary role in the pathogenesis of this rare disease. A new onset of hepatosplenomegaly combined with fever, fatigue, elevated liver enzymes, anaemia, or leukopenia in young IBD patients should raise the clinical suspicion of HSTCL after the exclusion of an infectious disease. Cancer According to a meta-analysis [66], 3.7% of UC patients (95% CI 3.2%–4.2%, n ¼ 54,478) in surveillance programs and tertiary centres suffer from colorectal cancer (CRC). However, recent population-based studies [67] indicate a rather low annual CRC incidence rate of 0.06%–0.16% in patients with UC. Additionally, patients with IBD have a four-fold increased risk of cholangiocarcinoma (2725 cases per 41,280 patients, RR ¼ 4.0, 95% CI 2.5–6.4) [68] and a 16-fold (4 cases per 1251 CD patients, SMR ¼ 15.6, 95% CI 4.3–40.1) [69] to 18-fold (5 cases per 2645 CD patients, SIR ¼ 17.9, 95% CI 5.8–42.0) [70] increased risk of small bowel adenocarcinoma. Additional immunosuppressive therapy may increase the risk of cancer, as shown in UC patients after liver transplantation [71]. In the controlled portions of clinical trials for all indications, including RA and IBD, the incidence rate of malignancies, excluding lymphoma and nonmelanoma skin cancer, in patients receiving infliximab (14 of 4019 patients, 520 per 100,000 patient-years) was higher than in the control groups (1 of 1597 patients, 110 per 100,000 patient-years) [51], but similar to that of the general population (RR ¼ 1.0, 95% CI 95% 0.67–1.43) [72]. Identical data exist on adalimumab with a malignancy risk of 0.6 per 100 patient-years among 3853 treated patients vs. 0.4 per 100 patient-years in the control groups according to the current prescribing information. In the meta-analysis of RCTs on infliximab and adalimumab in RA by Bongartz and colleagues [16], a more than three-fold increased risk of malignancy in patients treated with anti-TNF-a agents (pooled OR ¼ 3.3, 95% CI 1.2–9.1) was identified. The FDA criticized the study design and demanded an adjustment for duration and a comparison to the general population risk [72]. However, subsequent inclusion of two RCTs decreased the pooled OR for malignancy to 2.4 (95% CI 1.2–4.8, n ¼ 5788) [73], still implicating an increased risk of malignancies (including lymphomas and NMSC) compared to antiTNF-a-naı¨ve RA patients. In a similar meta-analysis of 21 placebo-controlled, randomized trials on biologicals in adults with CD [74], there was no difference in malignancies between the anti-TNF-a groups and the control groups (8/3341 patients vs. 8/2015 patients, 95% CI of the difference 0.45 to 0.18). However, safety data from the control groups of these RCTs have to be interpreted with caution because five of eight malignancies occurred in individuals that had previous anti-TNF-a exposure in open-label phases of the studies [74]. Case series and cohort studies report overall malignancy rates between 0% and 6% in anti-TNF-a treated patients (see Table 1), but most trials do not provide an adjusted estimation of expected cases in the general population. Two controlled cohort studies [15,75] and a matched-pair case-control study [76] demonstrated a non-increased overall risk of malignancy in IBD patients within a median follow-up of 24–52 months after the start of infliximab infusion: the crude pooled incidence for all reported malignancies was 37/1460 (2.5%) in the infliximab groups vs. 42/1287 (3.2%) in the infliximab-naı¨ve groups (Table 1). Data from the prospective, observational, multicentre TREAT registry on 3334 CD

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Table 1 Incidence of malignancies associated with infliximab or adalimumab treatment in recent cohort studies and cases series including  50 patients. Place

Indi-cation

anti-TNF-a agent

Patients with malignancies in anti-TNF-a cohort

Median follow-up in months

Risk estimation

Reported malignancies (solid cancers// hematological malignancies// skin cancers)

Colombel et al,[9] 2004 Kinney et al,[94] 2004 Ljung et al,[13] 2004 Seiderer et al,[95] 2004 Doumit et al,[75] 2005 Orlando et al,[96] 2005 Biancone et al,[76] 2006

USA USA Sweden Germany USA Italy Italy

CD CD IBD IBD CD CD CD

Infliximab Infliximab Infliximab Infliximab Infliximab Infliximab Infliximab

9/500a 0/117 3/217 0/92 7/322 (vs. 5/217) 8/573 9/404 (vs. 7/404)

17 12 N.R. 26 24 N.R. (6) 25

2 LuC, CUP//HL, NHL//4 NMSC -//-//-//3 NHL//-//-//N.R. (abstract) 3 BC, AC, LaC, CCC//L//NMSCd 3 BC, 2 AC, CCC, LaC//L//NMSCd

Cohen,[97] 2006 Pacault et al,[98] 2006 Caviglia et al,[99] 2007 Lichtenstein et al,[63] 2007 Caspersen et al,[91] 2008

USA France Italy USA

CD CD IBD CD

Infliximab Infliximab Infliximab Infliximab

12 35 N.R. 41 (10796 py)

Denmark

IBD

Infliximab

0/129 2/137 3/50 0.39/100 py (vs. 0.53/100 py) 4/651

29

Ho et al,[78] 2008 Karmiris et al,[79] 2008 De Vries et al,[100] 2008 Fidder et al,[15] 2009

Scotland Belgium Netherlands Belgium

CD CD IBD IBD

Adalimumab Adalimumab Infliximab Infliximab

2/98 5/148b 9/147 21/734 (vs. 30/666)

(100.5 py) 6.5 N.R. (abstract) 58

– – – – N.R. (abstract) – OR ¼ 1.33 (95% CI 0.46–3.84) – – – RR ¼ 0.74 (95% CI 0.49–1.12) SIR ¼ 0.7 (95% CI 0.2–1.7) – – – OR ¼ 0.97 (95% CI 0.56–1.65)

Lees et al,[10] 2009

UK

IBD

Infliximab

4/199c

29

–

-//-//EnC, TC//-//BC, EnC, GC//-//N.R. (abstract) CRC, EsC, OC//-//MM CRC, LuC//-//2 RCC, LuC, M//-//3 NMSCb 4 CRC, BC, Car þ SMC//-//2 NMSC, MM 2 BC, 2 CC, 2 MM, BC þ NMSC, CCC, CUP, EnC, PC, RCC þ NMSC//HL, L, NHL//6 NMSC 2 LuC//MDS, NHL//-c

Abbreviations: AC: Anal carcinoma, BC: Breast cancer, Car: carcinoid, CC: Cervical cancer, CCC: Cholangiocarcinoma, CUP: Carcinoma of unknown origin, CRC: Colorectal carcinoma, EnC: Endometrial carcinoma, EsC: Esophageal carcinoma, GC: Gastric cancer, HL: Hodgkin’s Lymphoma, L: Leukemia, LaC: Laryngeal carcinoma, LuC: Lung cancer, M: Meningioma, MM: Malignant melanoma, MDS: Myelodysplasia, NHL: Non-Hodgkin’s Lymphoma, NMSC: Nonmelanoma skin cancer, OC: Ovarian cancer, PC: Pancreatic cancer, RCC: Renal cell carcinoma, SMC: Small bowel carcinoma, TC: Thyroid cancer. N.R.: Not reported, OR: Odds ratio, py: Patient-years, RR: Relative risk, SIR: Standardized incidence ratio. a 3/9 attributed to infliximab use. b 7 malignancies in 5 patients. c additionally, one lung cancer and one cutaneous T-cell lymphoma occurred in patients treated with infliximab for refractory coeliac disease. d Possible cohort overlap.

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patients receiving infliximab over a mean follow-up of 3.4 years (10,796 patient-years) demonstrated a malignancy rate similar to CD patients not receiving infliximab (0.39 per 100 patient-years vs. 0.53 patient-years, respectively; RR ¼ 0.74, 95% CI 0.49–1.12) despite a higher disease activity (31.1% vs. 10.7% with moderate to severe disease, p < 0.0001) and a higher co-medication rate of prednisone and immunosuppressants (49.1% vs. 31.6%, p < 0.0001) in the infliximab group [63]. The most common reported malignancies in infliximab- or adalimumab-treated patients besides NHL, Hodgkin’s disease, and NMSC were breast cancer, colorectal carcinoma, malignant melanoma, prostate cancer, and lung cancer. In a multicentre RCT on infliximab in moderate to severe chronic obstructive pulmonary disease (COPD), nine of 157 infliximab-treated patients developed malignancies (four cases of lung cancer, two cases of laryngeal cancer) within 44 weeks of follow-up compared to one of 77 placebo-treated subjects [77]. Because these nine patients had a history of at least 40 packyears of smoking and seven cases were presumably tobacco-associated (four cases of lung cancer, two cases of laryngeal cancer, one case of renal cell carcinoma) [77], it is possible that infliximab contributed to the progression of pre-existing malignancies. Cases of lung cancer were also reported in several cohort studies on infliximab in IBD [9,10,78,79]. Although TNF-a antagonists have been evaluated in phase I and II cancer trials, the ECCO evidence-based consensus on the diagnosis and management of CD is that infliximab is best avoided in patients with a history of malignancy [80]. A strict follow-up of premalignant lesions of the colon, bladder, and cervix is required in patients that have been treated with TNF-antagonists. In a recent large matched case-control study on 77,590 individuals, it has been shown that women who used thiopurines or methotrexate in addition to corticosteroids have a 30%–40% increased risk of cervical abnormalities (OR ¼ 1.41, 95% CI, 1.09–1.81) [81]. Although the risk of abnormal PAP smears, abnormal cervical biopsy, or cervical cancer appears to not be increased in UC patients (OR ¼ 1.03, 95% CI 0.77–1.38) and in CD patients without the use of oral contraceptives (OR ¼ 0.48, 95% CI 0.30–0.76) [81], the effect of anti-TNF-a agents on the development of cervical premalignant and malignant lesions has not yet been evaluated conclusively. Miscellaneous complications A few miscellaneous side effects associated with biological therapy in IBD have been identified after the introduction of biologicals to the market. The use of anti-TNF-a agents has been associated with autoimmunity and the formation of antinuclear antibodies (ANA) and antibodies to double-stranded DNA. At present, there are no data to support routine ANA or anti-DNA-AB monitoring in clinical practise during anti-TNF-a therapy. Furthermore, patients frequently develop an antibody response against biological drugs. The immunogenicity is different for each drug, and the importance is not well understood for most molecules. It is comprehensible that antibodies can interfere with the pharmacokinetics of the drug and hence with its effects. They may also be the cause of acute and delayed infusion reactions and injection site reactions. In an excellent review, Vermeire and co-workers [82] describe strategies for clinicians to administer these therapeutics most effectively and to minimise the problems associated with antibody formation. While the development of antinuclear and, less frequently, of anti-DNA antibodies is a common finding, the onset of autoimmune diseases during biological treatment is a rare event, which needs to be promptly recognized in order to plan the appropriate management. Neurological disorders following application of biologicals have been described. Demyelinating diseases occur more commonly among patients with IBD [83], and demyelinization of peripheral nerve bundles and optic neuritis are clearly associated side effects of anti-TNF-a agents. Therefore, patients presenting with symptoms of sensory or motor neuropathy should be carefully evaluated before initiation of anti-TNF-a treatment. Further, the use of biologicals has been associated with an increasing number of cases of autoimmune diseases, such as cutaneous vasculitis, systemic lupus erythematosus, lupus-like syndrome, sarcoidosis, uveitis, and isolated cases of thyroiditis and interstitial lung disease. Anti-TNF-a treatments are efficacious in the treatment of psoriasis and psoriatic arthritis. However, recent case reports describe the occurrence of psoriasis as an adverse event in patients receiving antiTNF-a therapy. The FDA is currently reviewing 69 cases of new onset psoriasis, including pustular (17 cases) and palmoplantar (15 cases) subtypes, in all patients using TNF-a blockers for the treatment of autoimmune and rheumatic conditions other than psoriasis and psoriatic arthritis [50]. Fiorino et al.

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[84] summarized that the risk and incidence of anti-TNF-a-induced psoriasis in patients with IBD was 0.102 patient/year/duration, meaning that these are rare adverse events. However, Sherlock and coworkers [85] described that 13 of 118 children developed psoriasis following infliximab therapy. A number of possible explanations for the paradoxical occurrence of psoriasis as an adverse event of antiTNF-a treatment have been explored by other authors. The possibility of misdiagnosis of the primary rheumatological disease exists, and psoriatic arthritis may precede psoriasis in approximately 15% of cases. Alternatively, the patients with psoriasis as an adverse event may have a genetic predisposition to psoriasis, which, after all, is not uncommon (prevalence 2.5%), in addition to their arthritis [86]. Others have suggested that the adverse event is not psoriasis, but is instead either a drug hypersensitivity reaction such as acute generalised exanthematous pustulosis [87] or a bacterial infection caused by inhibition of TNF-a [88]. Liver toxicity has been linked to infliximab and, to a lesser extent, to adalimumab treatment. Cases of infliximab-induced hepatitis and liver failure have been reported in patients with IBD or rheumatoid arthritis [89]. Furthermore, during pivotal trials, liver enzyme elevations five-fold higher than the upper the limit of normal values were observed in 1–4% [51]. Clinical trials with anti-TNF-a antibodies in patients with chronic heart failure have disclosed the potential of aggravating severe heart failure with excess mortality. Therefore, the use of anti-TNFa agents in heart failure (NYHA class III and IV) is contraindicated [90]. Mortality While the safety profiles discussed above deal with morbidity, the ultimate measure by which to assess the impact of biologicals in IBD patients is death. In a large single centre study evaluating the long-term safety of infliximab in IBD patients treated with infliximab over a 14-year period, 12 of 743 patients treated with infliximab (1.6%, 0.3 per 100 patient-years) died compared to 16 of 666 patients (2.4%, 0.2 per 100 patient-years) in the control group [15]. Because patients with an expected high short-term risk of death are typically not put on biologicals in clinical practise, a reduced short-term mortality is expected. In contrast, in a Danish cohort study [91] of 651 patients, a standardized mortality ratio of infliximab-treated IBD patients was 1.9 (95% CI 1.0–3.2). However, it is important to note that among the unselected patients with CD, overall mortality was slightly higher than in the general population [92]. In a recent retrospective cohort study [93] on anti-TNF-a agents among patients with ocular inflammatory diseases, an increased overall mortality (adjusted HR 1.99, 95% CI 1.00–3.98) and an increased cancer-related mortality (adjusted HR 3.83, 95% CI 1.13–13.01) were reported. Because patients receiving anti-TNF-a therapy had a high co-morbidity index, were often exposed to alkylating agents, and were observed over a relatively short follow-up period, these data should be interpreted with caution. In contrast, a meta-analysis of anti-TNF-treatment in all indications described no increased risk of death following treatment with adalimumab [20]. Conclusions The side effects of biologicals can be severe; therefore, careful consideration and monitoring can partially prevent damage. Abscesses and opportunistic infections should be treated, and screening for tuberculosis and for hepatitis B and HIV in high-risk patients is mandatory before the start of treatment. The potential risk for malignancies and infections during anti-TNF-a therapy appears to strongly increase with concomitant immunosuppressive therapy, such as treatment with thiopurines. Therefore, risk stratification in order to reduce side effects in IBD patients requiring immunosuppressive therapy will become an important part of long-term treatment in these patients. Funding source Professor Stallmach consults, has received research support, and has lectured for Abbott, Essex, Schering Plough, and UCB.

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Conflict of interest statement The authors disclose no conflict of interests.

Practice points  A careful clinical evaluation upon starting anti-TNF-a therapies is recommended  Anti-TNF-a agents should be used with caution in patients with pre-existing SLE and should not be used in patients with pre-existing malignant or premalignant disorders  The most common adverse effects during biological therapy are as follows: – bacterial and fungal infections (reactivated tuberculosis, aspergillosis, histoplasmosis, cryptococcosis, candidosis, listeriosis, pneumocystosis) – development of solid cancers, lymphomas, and leukemia – slightly increased mortality (similar to untreated patients)

Research agenda The following aspects related to the use of biological therapy in IBD have not been adequately understood and need further investigation:  Predictors of response to biological therapies in patients with IBD could improve the selection of patients with a higher probability of favorable outcomes and could, therefore, improve the safety profile.  Is there a correlation between drug serum levels of biologicals and/or the cumulative dose and the occurrence of complications or are patient characteristics (genetic profile, environmental factors, co-medication) responsible for complications such as cancer and infections?

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