St James's Hospital and Trinity College Dublin, Institute of Molecular Medicine, Dublin, Ireland.
Correspondence to: St James's Hospital (CREST), James's St., Dublin 8, Ireland. E-mail: jkeane{at}stjames.ie
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Abstract |
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KEY WORDS: Tuberculosis, TNF
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Introduction |
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In this paper, we review the data that link the use of TNF blockers and the progression or reactivation of latent tuberculosis infection (LTBI) to tuberculosis disease, and consider the scientific evidence that makes this a plausible link. Reactivation of LTBI is a controllable public health issue in low-prevalence countries, and so the emergence of this issue with TNF blockers can be addressed (with screening for and prophylactic treatment of LTBI). More and more countries are publishing guidelines to assist TNF blocker prescribers in making these drugs safer, and we comment on some of this advice.
Our discussion will focus on the newer TNF blockers, or biologics; namely infliximab and adalimumab, which are anti-TNF monoclonal antibodies (mAb), and etanercept, which is a soluble TNF receptor (sTNFR).
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The link between TNF blocker use and reactivation tuberculosis |
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Countries that seek to eliminate tuberculosis have active programmes to treat LTBI in groups that are at a high risk of reactivating disease. In this context, patients taking TNF blockers have been singled out as a group that require special attention [9]. Tuberculosis is a public health issue, so identifying at-risk groups (targets for screening, evaluation and possible treatment for LTBI) will impact on community health as well as that of the patient. For this reason, there is merit in reviewing the association between TNF blockers and tuberculosis, and considering strategies to deal with this problem. The association of TNF blockers and reactivation of tuberculosis has already led to national initiatives in some countries to guide clinicians on how to deal with this issue [1013].
Infliximab
Infliximab has been licensed by the US Food and Drug Administration (FDA) since 1998 for the treatment of rheumatoid arthritis (RA) and Crohn's disease. Infliximab is a monoclonal antibody that can bind to different species of TNF, including free TNF, transmembrane TNF (tmTNF) and TNF that may be bound to its receptor [14]. The off rate for this drug-receptor binding is low and the elimination half-life of the agent is about 210 h. In 2001, we reported 70 cases of tuberculosis with infliximab [5] and subsequently 117 cases of tuberculosis, up to November 2001, in the setting of this agent [15]. Wallis et al. have identified 335 cases up to September 2002 [2, 16]. Most of these cases were thought to be due to the progression or reactivation of LTBI to tuberculosis disease, and the median time from initiation of TNF blocker therapy to the diagnosis of tuberculosis was about 12 weeks.
Reports of these cases came from the FDA Adverse Event Reporting System, which relies on passive reporting from clinicians. Because it is a passive reporting system, it can be assumed that the issue is under-reported, by an unknown amount. The reports primarily come from US health-care providers and consumers to FDA or to pharmaceutical manufacturers, which then forward the reports to FDA, but data on patients from other countries may also be reported.
The pooled data from clinical trails of infliximab are available in the revised Remicade label [17]. This reports on six patients who got tuberculosis in this setting and also suggests that the tuberculosis was reactivation of LTBI. Of 924 patients receiving infliximab in the trial, 0.4% developed tuberculosis, compared with none in the placebo arm.
The initial analysis of the 70 patients reported to have developed tuberculosis on infliximab demonstrated a predictable pattern of disease for patients that are immunosuppressed [5]. That is to say, most of the patients developed extrapulmonary tuberculosis disease, and nearly a quarter had disseminated disease. This compares with 15% extrapulmonary disease and less than 1% disseminated disease in immunocompetent individuals [18]. Patients developed tuberculosis in countries with a low background rate of tuberculosis. Wolfe et al. have recently compared background tuberculosis incidence rates in US RA patients untreated with infliximab, and the reported tuberculosis rate in US RA patients treated with infliximab [19]. The background RA rate was 6.2 tuberculosis cases per 100 000 patients per year, compared with the infliximab-treated RA reported rate of 52.2 per 100 000 patient-years of exposure. Wallis et al. have confirmed a similar US reported rate of tuberculosis in infliximab as 54 per 100 000 treated patients [2, 16]. Histoplasmosis is an infection that can be walled off in granulomas, just like latent tuberculosis infection. A convincing association of histoplasmosis reactivation and infliximab use has also been reported which supports the association of the mAb use and reactivation of latent infection [20]. The data for listeriosis and coccidioidomycosis also appear to support the special susceptibility that infliximab-treated patients have for infectious diseases that rely on granuloma for host defence [21].
The salient feature of tuberculosis, over other infectious disease complications, is remarkable. It supports the notion that infliximab results in compromise of granuloma function and in breaching the integrity of this cellular compartment, which normally confines viable, but latent, bacilli.
Adalimumab
Adalimumab is also an mAb product, and in clinical trails its use was associated with reactivation tuberculosis [22]. Trial data showed that the median time to onset of reactivation from LTBI to disease was about 46 months before LTBI screening and prophylaxis was introduced. A doseresponse of the drug and tuberculosis was seen: more patients reactivated tuberculosis on a higher dose of the agent, and there was less tuberculosis reactivation seen on a lower dose.
These clinical data support but do not prove a causal association between the use of mAb TNF blockers and tuberculosis reactivation. The package inserts for infliximab and adalimumab contain advice on screening for LTBI in all patients considered for treatment. This is especially important as it prevents patient as well as public health morbidity and mortality from tuberculosis [23].
Etanercept
Etanercept is an sTNFR that binds soluble TNF [13]. It also binds tmTNF; but it may leave binding sites free [13]. The FDA has reported a number of post-marketing episodes of tuberculosis in the setting of its use [24]. Reported rates are passive and probably underestimate the incidence of tuberculosis on the drug, but Mohan et al. conclude that there is currently inadequate data to demonstrate a definite association between the use of the drug and reactivation tuberculosis [24]. No cases of tuberculosis disease were found in clinical trials of RA involving 3280 patients in the USA and Europe. A single case of tuberculosis was reported in a European patient involved in a clinical trail of therapy for congestive heart failure. The cases of tuberculosis seen with etanercept occurred with a less tight temporal association with the commencement of the drug. The median time to onset of tuberculosis was 46 weeks.
Comparing the rates
Is there a difference between the rate of tuberculosis after use of the mAb TNF blockers and the sTNFR? This issue has not been addressed in the setting of a prospective controlled trial, and comparisons are limited by methodological differences between the studies, so strong conclusions cannot be drawn. Relying on passively reported cases of tuberculosis can mislead and it is especially important to compare treated populations with the same distribution of risk factors for LTBI and reactivation if infected, if we are to attempt an answer to this question.
Infliximab was initially used extensively in Europe, where LTBI is substantially more prevalent, and etanercept was used mostly in the USA, which has a relatively low rate of LTBI. To allow for this discrepancy, Wolfe et al. looked at the reported infliximab-related rates of tuberculosis in the US RA population exclusively. They suggested that there is an increased reported rate in this group for infliximab vs RA patients that were not on the mAb (52.5 vs 6.2 tuberculosis cases per 100 000 patients) [19]. Wallis et al. have confirmed this in US-treated patients and reported tuberculosis rates of 54 and 28 per 100 000 treated patients for infliximab and etanercept respectively [16]. Gomez-Reino et al. compared rates for the two agents in a country of high tuberculosis rates (21 cases per 100 000 per year background) and concluded that infliximab increased the rate of tuberculosis in their patients, treated in Spain [25].
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Mechanism of tuberculosis susceptibility and TNF blockers |
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TNF elaborates important host response mechanisms
Before the emergence of tuberculosis as an important issue for patients on TNF blockers, there was a considerable amount of data that suggested that TNF was crucial in the innate immune response and maintaining latency of LTBI in animals. TNF was shown to be important in regulating chemokines [26], increasing adhesion molecule expression [27], mediating macrophage apoptosis (which can kill the infecting bacillus) [5, 28] and limiting excessive type 1 immune activation during intracellular infection [29]. These processes support a beneficial outcome for the host, and some of these in vitro observations foreshadowed the consequence of interfering with TNF activity in the setting of Mtb infection.
TNF is crucial to antituberculosis immunity in vivo
Numerous laboratories have performed experiments with mouse models of tuberculosis that confirm that TNF plays a crucial role in the immune defence against Mtb. The targeted deletion of TNF and its receptor have shown that the cytokine is necessary to mount a normal primary immune response to Mtb [30, 31]. It is more difficult to model LTBI in the animal model, but Mohan et al. have demonstrated in a mouse model of reactivation tuberculosis that blocking TNF activity using a monoclonal anti-TNF antibody resulted in reactivation [32]. The mechanism of this effect appeared to be due, in part, to poor organization of lung immunocytes, though not necessarily an increased bacillary load. Subsequently, the same laboratory has shown how TNF controls the level of chemokines that call in helpful immune cells to deal with Mtb infection [33]. Pentoxifylline has TNF blockade activity and Turner et al. have shown in a mouse model of LTBI that this agent can also cause reactivation tuberculosis [34]. TNF is considered to be a pro-inflammatory cytokine, yet in the setting of tuberculosis disease it has also been shown to play an important disease-limiting effect [29].
Investigators have studied which TNF species are adequate to allow good immunity against Mtb. In a knock-out-knock-in experiment, Olleros et al. engineered a mouse to only have tmTNF and no secreted TNF or lymphotoxin [35]. These animals had efficient cell-mediated immunity and resistance to Mycobacterium bovis Bacillus CalmetteGuerin. This suggests that tmTNF is enough to allow good immunity against tuberculosis. Of interest, infliximab neutralizes tmTNF but etanercept has a high off-rate on binding tmTNF [13].
TNF blockers and their pharmacological effects
The study of TNF blocker pharmacology and mechanisms of action may help us understand how these agents might be associated with tuberculosis. mAb blockers may be more associated with tuberculosis than sTNFR [16]. It has been suggested that the dose of infliximab is simply higher than the dose used of etanercept, yet both classes of agent treat the TNF-mediated diseases with similar efficacy. The drug classes differ in their half-lives (the elimination half-life of infliximab is 210 h and that of etanercept is 115 h) and pharmacokinetics. Infliximab is dosed at intervals of 8 weeks and etanercept was dosed, until recently, twice weekly for RA patients (etanercept is now given once weekly). This may mean that the TNF neutralization seen with mAb has a longer and more unrelenting duration of action. This profile of continuous blockage with mAb may prevent the granuloma from recovering its compromised integrity. In contrast, it has been speculated that TNF blockade with etanercept may allow the granuloma to reconstitute itself, thus preventing bacillary dissemination. Infliximab may bind free TNF, transmembrane TNF (tmTNF) and receptor-bound TNF in an irreversible manner [13]. In contrast, etanercept many bind only sTNF well and other species in a reversible manner, with a high off-rate [13]. This may contribute to more comprehensive neutralization of TNF in infliximab-treated patients, and in their tuberculosis granulomas specifically. These theories lack hard data, and they will need to be studied in animal models of tuberculosis. Already, animal studies have suggested that partial rather than complete TNF blockade may allow preservation of the beneficial and anti-inflammatory functions of this cytokine in tuberculosis immunity [29].
TNF blockers and their impact on immunity
As mentioned above, TNF blockers may cause reactivation tuberculosis by blocking TNF. However, other indirect effects of TNF blockers in immunity may also contribute to reactivation. The mAb blockers can cause complement-mediated and antibody-mediated killing of cells [13]. In addition, they have been shown to cause monocytopenia [36] and T-cell death ex vivo [37]. Both of these cell types are important in maintaining granuloma, and there could be negative consequences for tuberculosis immunity if the drug killed them. Other studies of patients treated with TNF blockers suggest that infliximab may affect other important protective aspects of the host defence, such as Th1 skewing of T cells [38] and interferon- (IFN-
) activity [4]. However, it has been reported that IFN-
levels are low in RA patients who are TNF blocker-naive [39]. The results of these studies in TNF blocker-treated patients will require more careful control for the underlying immune defects that are present in patients because of their coexisting autoimmune condition. Wood et al. have studied the function of macrophages isolated from patients taking TNF blockers. They found significantly suppressed IFN-
responses and a lack of the protective Th1 responses that are normally associated with a successful immune response to tuberculosis and fungi such as histoplasmosis [40].
TNF blockers and drug synergy
It is possible that the emergence of tuberculosis in this setting may just reflect the addition of another immunosuppressant to an existing immunosuppressive regimen. For the treatment of RA, infliximab is licensed in the USA for use only with methotrexate (for Crohn's disease, infliximab is licensed for use alone). Etanercept can be used alone, yet these patients are also frequently on other immunosuppressants. Drugs like methotrexate may synergize in immunosuppression to interfere with granuloma integrity. Against this argument is the propensity of these agents to reactivate tuberculosis as opposed to other infections [16]. Bergstrom et al. failed to demonstrate a synergistic effect of other immunosuppressants on coccidioidomycosis cases taking TNF blockers [41]. For now, it is unclear what role, if any, drug synergy plays in TNF blocker-reactivation tuberculosis.
A deeper understanding of these different mechanisms will improve the safety of these agents and inform us of the basic pathobiology of tuberculosis.
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Dealing with TNF blockers and tuberculosis in the clinic |
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Screen and treat LTBI in patients on TNF blockers
Screening for LTBI is advised in all patients before the use of TNF blockers [43]. This should include a careful history (looking for exposure to Mtb), a tuberculin skin test (TST) and a chest radiograph. The presence of LTBI is considered likely if the TST is positive and the chest X-ray is normal. LTBI should be treated with prophylaxis if possible, and a good option is 9 months of isoniazid (INH), but local regimens for prophylaxis differ [8]. In Europe, the EMEA (European Medicines Agency) have developed a useful patient alert card for patients on infliximab, which will help in managing LTBI (see http://www.emea.eu.int/pdfs/human/press/pus/003202.pdf). It is advisable that all TNF blocker prescribers familiarize themselves with local recommendations, and attempt to treat LTBI when present. This approach helps minimize the number of avoidable tuberculosis cases in this vulnerable group. Biologic agents are costly, but the cost of screening and treating for LTBI should be factored into their use. TNF blockers should not be used until active tuberculosis has been ruled out or completely treated, if present. This may require sending sputum for culture. In the diagnosis of LTBI in adults, childhood BCG vaccination should be ignored. For example, BCG vaccination at infancy probably does not explain a positive TST in a 25-yr-old. Gardam et al. suggest that it is preferable to complete the course of prophylactic treatment in patients with LTBI before starting a TNF blocker, but concede that clinical conditions may warrant introducing the new immunosuppressant sooner [44]. In this setting is seems wise to start the TNF blocker after 12 months of LTBI treatment, to see if the antituberculosis therapy is well tolerated [44].
Is screening working?
The impact of screening for LTBI prior to initiating TNF blocker therapy has been reported recently. Perez et al. have suggested a more than 90% reduction in tuberculosis reactivation after screening in Germany [23]. Gomez-Reino et al. have also reported a decrease in tuberculosis cases after the publication of guidelines, in Spain, that promote prophylactic treatment [25].
Balancing LTBI treatment risk and consequences
INH is potentially hepatotoxic, which would argue for avoiding prophylaxis treatment in the indigenous population of countries with a low tuberculosis prevalence. Yet there are potentially consequences of failing to treat LTBI in this patient group that need consideration. High mortality rates in this group have been reported (12%) [25] and disseminated disease may be initially refractory to treatment because of lingering TNF blocker in the system [45]. Tuberculosis is a public health issue, and failed treatment could lead to an outbreak in a family, or indeed in other immunocompromised patients that the TNF blocker-treated patient may be in contact with. The use of antituberculous medication in these patients is often complex, and it would be beneficial to seek the advice of a tuberculosis specialist in their care.
The tuberculin skin test
Use of the TST has some shortcomings, but it is widely available and helpful when positive. It therefore should be employed, for lack of a better-proven option. It is difficult to make advice on TST interpretation globally applicable because different countries use different preparations and different concentrations (i.e. 2 TU versus 5 TU) in the test. Specifically, a strict cut-off of 5 mm induration being positive is recommended [46] and endorsed by others [47], in the setting of planned TNF blocker use, in low-prevalence countries. The effects of immunosuppressive treatment and autoimmunity are likely to result in a high rate of false-negative TST test results.
Although there are currently no data to support the treatment of such patients with prophylactic INH, a negative TST result in this setting should be considered suspect. These patients should be carefully monitored for an unusual presentations of tuberculosis. This is an example of a test for which absence of evidence is not evidence of absence. The prescriber must therefore remain vigilant for tuberculosis, as the development of disease in this vulnerable group may be associated with more morbidity and mortality than normal. Patients should be advised to seek medical attention if night sweats, weight loss or respiratory symptoms develop on these agents, so that investigation for tuberculosis may be performed. The myriad extrapulmonary presentations reported suggest that clinicians also need to think TB in a variety of clinical presentations in these patients.
The inadequacies of the TST have been the impetus behind the development of newer tests for LTBI, such as QuantiFERON [48] and the ELISpot test [49]. Their success in the setting of chronic inflammatory disease and immunosuppressive treatment needs further investigation.
Treating LTBI as a priority
By focusing on LTBI and the immunocompromised patient, it is hoped that improved prescriber awareness will be generated to prevent reactivation tuberculosis among patients with chronic inflammatory disease who take old and new immunosuppressive agents. This is especially important as TNF blockers become licensed for more and more diseases, and new TNF blocker treatments are being developed, such as TNF vaccines and anti-TNF proteases. The issue of reactivation of tuberculosis may also be germane to newer anti-inflammatory mAb that target other cytokines that play a key role in tuberculosis immunity [50].
Treatment of LTBI will afford the majority of patients (70%) protection from reactivation tuberculosis from their infection, which is also to the benefit of their communities. It should be made clear to the patient that complete prevention is not possible, as patients have been reported who reactivated tuberculosis despite treatment with INH [51]. There are few data to support the treatment of patients who fail to fulfil the criteria for LTBI, yet it seems prudent to treat patients who have RA and who are treated with TNF blockers when there is a definite history of exposure to a case of infectious tuberculosis [47].
Recently attention has been drawn to poor completion rates for LTBI in the general population (about 30%) [9]. Nonetheless, the regular attendance at a tuberculosis clinic, if available, should improve completion rates in this group, for whom finishing treatment is especially important. In some cases, directly observed treatment of LTBI may be required. This is not to say that patients should be deprived of autonomy, because, in contrast to treating infectious tuberculosis, there is no direct transmission risk at all with LTBI.
Should LTBI be treated in patients on sTNFR blockers?
Mohan et al. supports caution with the use of sTNFR blockers and appropriate measures to avoid tuberculosis [24]. This would support the prudent step of screening and treating LTBI in this group as well as those on mAb. Furthermore, it is probable that many chronic inflammatory diseases themselves interfere with the immune response.
Are patients with RA more likely to reactivate LTBI?
The tuberculosis rates for RA patients do not appear to be higher in the USA compared with background rates [19], but this analysis does not compare groups with the same demographic background. Data from high-prevalence countries suggest that reactivation tuberculosis is more common in a group of patients with autoimmune disease [52]. For these reasons, it may be helpful to screen and treat for LTBI in RA patients regardless of TNF blocker treatment, in high-prevalence countries.
Treating tuberculosis disease in patients on TNF blockers
The development of tuberculosis in vulnerable patients on immunosuppressive therapy is a concerning development, but sometimes unavoidable. The isolation of the organism remains a priority and special note is made of the likelihood of positive blood cultures in this setting. A high index of suspicion for the presence of tuberculosis, often presenting in an unusual way, and its prompt treatment will save lives. This rare complication should be balanced against the massive benefit that ill patients can potentially get from these biological agents.
Primary tuberculosis, exogenous reinfection and inactive tuberculosis disease
The association of tuberculosis and TNF blockers is especially important in countries of high LTBI prevalence. Physicians in these areas have to contend with the possibility of increased susceptibility to primary tuberculosis or exogenous tuberculosis reinfection [53] on TNF blockers, as well as reactivation tuberculosis. If prescribers successfully treat LTBI in these countries, they may not be complacent. This is because their patients remain at risk of a new Mtb infection, even after they have successfully dealt with LTBI.
The theoretical possibility that TNF blockade would increase the susceptibility to primary tuberculosis has a good foundation in animal models of disease [30]. Only continued data-gathering from clinical use will inform about an association of primary tuberculosis disease with TNF blockade.
A chest radiograph should be performed on all patients before TNF blocker therapy. This is because some patients will have findings that suggest old, healed tuberculosis and they may not have received antituberculosis treatment in the past. These patients are especially vulnerable to tuberculosis reactivation and should be offered treatment to sterilize the old lesion of viable Mtb [9]. Regimens vary but include 9 months of INH, or two antituberculosis drugs (e.g. rifampicin with or without INH) for 4 months, which will decrease the chance of reactivation [8]. A regimen that used rifampicin and pyrazinamide for 2 months has been shown to cause unacceptable hepatoxicity [54].
TNF blockers as treatment in tuberculosis disease
Excess TNF appears to damage the host in advanced tuberculosis disease. Tuberculosis causes ill-health through weight loss and night sweats, which may be due to excessive TNF activity. Thalidomide, which is a drug with TNF blocking properties, has been shown to improve some outcomes in the setting of advanced tuberculosis disease [55]. Recently, in a pilot study, etanercept appeared to improve the health of HIV-infected patients with tuberculosis, presumably by interfering with this negative effect of TNF [56]. This is consistent with the notion that TNF plays a crucial positive role in host defence during primary infection and in maintaining latency, whereas excessive TNF during tuberculosis disease is detrimental to the host. This is also a good example of how, for cytokines, their meaning is controlled by context [57]. This apparent benefit seen with TNF blockers in tuberculosis disease highlights the difference in pathobiology of tuberculosis and the sepsis syndrome, where TNF blockade did not improve outcome [58].
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Acknowledgments |
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The author has received speaker's fees from Wyeth and Centocor.
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