Review article: minimizing tuberculosis during anti-tumour necrosis factor-alpha treatment of inflammatory bowel disease

Authors


Prof. J. M. Rhodes, School of Clinical Science, University of Liverpool, Duncan Building, Daulby Street, Liverpool L69 3GA, UK.
E-mail: rhodesjm@liverpool.ac.uk

Summary

Background  Tumour necrosis factor (TNF)-alpha inhibitors are a major advance in the management of inflammatory bowel disease but increase the risk for tuberculosis (TB).

Aim  To examine the reasons for the increase in the risk for TB and the strategies to reduce it.

Methods  PubMed searches were performed using search terms that included TB and each of the current anti-TNF-alpha biological agents and also TB and Crohn’s disease.

Results  Increased susceptibility to TB, often with extrapulmonary or disseminated disease, occurs following treatment with all anti-TNF-alpha biological agents and amounts to a four- to 20-fold increased risk with infliximab. TB usually occurs shortly after anti-TNF-alpha initiation suggesting reactivation of latent infection. Animal studies show that TNF-alpha inhibition impairs inflammatory cell trafficking and granuloma formation. Currently recommended screening for latent TB typically, risk assessment, tuberculin skin testing and chest radiograph used prior to anti-TNF-alpha treatment can reduce TB rates by up to 90% but newer screening interferon gamma assays may enhance screening efficacy. Patients positive on screening who are treated with isoniazid and subsequently receive anti-TNF-alpha treatment still have approximately 19% risk for TB.

Conclusions  Tuberculosis following treatment with TNF-alpha inhibitors usually results from reactivation of latent disease. Screening reduces the risk substantially but does not completely eliminate it.

Introduction

For about 50 years, glucocorticoids have been the principal short-term therapy for acute inflammatory bowel disease (IBD) and immunosuppressants such as azathioprine and methotrexate have increasingly been added to help maintain remission. Despite these therapies, symptom control is suboptimal with only about 42–64% of Crohn’s patients being symptom free at any one time.1, 2 Moreover, the need for intestinal surgery because of failure of medical therapy has probably not changed significantly over the past 20 years.3 The advent of anti-tumour necrosis factor alpha (TNF-alpha) therapy has provided a new therapeutic approach that is often dramatically effective1, 2, 4–6 but which has also brought new concerns regarding safety.

TNF-alpha is present at high levels in the intestinal mucosa of patients with IBD7–9 and large randomized controlled trials have demonstrated the efficacy of the anti-TNF-alpha monoclonal antibody infliximab in the treatment of refractory and fistulating Crohn’s disease as well as in the management of ulcerative colitis.4–6 Adalimumab and certolizumab pegol, two newer anti-TNF-alpha antibodies, have proved beneficial in moderate to severe Crohn’s disease.10–15 In contrast, the injectable TNF-alpha receptor fusion protein etanercept has not been found to be of benefit in Crohn’s disease, but is widely used in rheumatoid arthritis.16 This implies that the efficacy of anti-TNF-alpha agents in Crohn’s disease may not be simply the result of TNF-alpha inhibition; apoptosis of monocytes and T lymphocytes bearing transmembrane TNF-alpha has been proposed as an alternative explanation.17

Treatment with TNF-alpha antagonists has also been used to great effect in other inflammatory conditions, such as rheumatoid arthritis, the spondylarthropathies and psoriasis. However, as patient exposure to TNF-alpha inhibition has increased, it has emerged that it is not without problems. There is an increased risk for TB, other forms of sepsis including histoplasmosis, coccidiomycosis and listeriosis7, 18, 19 and an increased risk for the otherwise rare hepatico-splenic T-cell lymphoma.20, 21 This review focuses on the reasons for development of tuberculosis (TB) and methods to reduce its occurrence in patients receiving anti-TNF-alpha therapy.

Methods

Relevant publications for review were identified using the PubMed database. English-language papers only were reviewed using the following keywords alone or in combination: ‘tumo(u)r necrosis factor alpha/TNF-alpha and tuberculosis/TB/mycobacterial infection’, ‘tuberculosis/TB/mycobacterial infection and infliximab/etanercept/adalimumab/certolizumab’, ‘TNF-alpha antagonists/inhibition/anti-TNF and tuberculosis/TB/mycobacterial infection’, ‘tumo(u)r necrosis factor inhibition/blockade/antagonists and tuberculosis/TB/mycobacterial infection’, ‘anergy and Crohn’s disease/IBD/ulcerative colitis’, ‘TST/Tuberculin skin test and tumo(u)r necrosis factor inhibition/antagonists’, TST/Tuberculin skin test and latent TB/tuberculosis’‘latent tuberculosis treatment’, ‘tuberculin skin testing’, ‘interferon gamma assays’, ‘QuantiFERON TB-Gold’, ‘T-Spot.TB’. In particular, all 382 papers identified using search terms ‘tuberculosis and Crohn’s’ in title or abstract were studied. All 15 of these that were relevant to TB complicating Crohn’s disease or its treatment were then included. Further data on TB incidence and safety of adalimumab and certolizumab were obtained by searching the WHO, Centre of Disease Control (CDC), FDA, Abbott pharmaceuticals and UCB websites.

Tuberculosis rates in control populations and anti-tumour necrosis factor-alpha-treated patients

It is estimated that one third of the world’s population has latent TB infection.21 The World Health Organization estimated incidence of active TB for 2005 ranged from 50 per 100 000 in Europe to 343 per 100 000 in Africa.22–24 However, most (90%) of the affected individuals develop latent rather than active disease, with encapsulation of viable TB bacilli within granulomata. Active disease may develop in patients with latent TB following immunocompromise and accounts for about 2 million deaths worldwide annually.24

Incidence studies of TB in inflammatory conditions have so far been confined mainly to mixed or rheumatoid arthritis populations. Studies in the USA have demonstrated a background rate of six cases of TB per 100 000 per year in the rheumatoid arthritis patient population.25 Keane and colleagues compared this to data received up to 2001 by the US Food and Drug Administration Adverse Event Reporting System (US FDA AERS); they found 70 reports of TB and calculated that patients with rheumatoid arthritis treated with infliximab, at 24 cases per 100 000 per year, had an approximately fourfold increase in the rate of TB. Of the 70 reported cases, 40 (57%) had extrapulmonary disease and 17 (24%) disseminated disease; this is in contrast to TB in non-immunocompromised populations where extrapulmonary disease affects about 15% and disseminated TB 1%.19, 26, 27 Similarly, Wolfe et al.28 calculated a TB incidence rate of 53 cases per 100 000 patient years in infliximab treated rheumatoid arthritis patients in the US and again found a high proportion (75%) with extrapulmonary disease. Gomez-Reino et al.,29 looking at the higher risk Spanish population, reported a much higher relative risk of 90.1 for TB in rheumatoid arthritis patients treated with infliximab compared with the general population and a relative risk of 19.9 compared with patients with rheumatoid arthritis. In Sweden, a low risk area for TB, Askling et al.30 reported a fourfold increased risk for TB in patients with rheumatoid arthritis treated with TNF-alpha antagonists. Again, relatively high rates of extrapulmonary (33%) and disseminated (13%) TB were seen. A smaller study looking at patients treated with infliximab for spondyloarthropathies reported 2 cases of tuberculosis amongst 107 patients.31

The wide variation in TB rates observed amongst different populations reflects the effect of ethnicity and country of origin on the incidence of latent TB infection. Interestingly, the Mayo experience in 500 patients with Crohn’s disease (CD) on infliximab did not record any cases of TB.32 Similarly, the TREAT registry has so far reported no cases of tuberculosis in 5807 CD patients, including 2850 who had received infliximab.33 A smaller German trial looking at one hundred patients with IBD also demonstrated no cases of tuberculosis.34 This raises the possibility that the risk for TB after anti-TNF treatment may be substantially lower amongst CD patients compared to those with rheumatoid arthritis, perhaps partly because of the younger age of the CD patients. This is borne out by the study by Keane et al where only 18 (26%) of postinfliximab TB cases were in patients with CD whereas CD accounted for 63% of the infliximab-treated population that was studied.25 There are no studies as yet on risk of TB postinfliximab in ulcerative colitis, but at present, it would seem reasonable to assume that the risk may be similar to that in Crohn’s disease.

The increased susceptibility to TB and its atypical presentation are not limited to infliximab, but are common to all TNF-alpha antagonist therapies (Table 1). Wallis et al examined the US FDA AERS data from 1998–2002 and noted that granulomatous infections in general, and specifically TB, were found with increased rates in patients treated with either infliximab (14% of whom had Crohn’s disease) or etanercept (none of whom had IBD) with rates of 144 and 35 per 100 000 patients respectively vs. a background rate of six per 100 000 population. Cases of TB were clustered shortly after initiation of treatment with the TNF-alpha antagonist, 72% occurring within 90 days, suggesting that disease occurred as a result of reactivation of latent disease, a finding confirmed by other researchers.19 By 2002, 25 cases of TB had been associated with etanercept use (although none of these cases occurred in patients with IBD) after its introduction to the market yielding a rate of 10/100 000 patient years; again with a high proportion of extrapulmonary and disseminated disease.35 This was in contrast to the absence of cases of TB in clinical trials in over 3000 patients with rheumatoid arthritis using etanercept.36 Fewer data are available regarding the newer anti-TNF-alpha antibody adalimumab, but this probably carries a similar increased risk of TB reactivation to infliximab with most cases occurring in the first 8 months after commencement of adalimumab therapy and the rate for extrapulmonary TB again being elevated at 27%.28, 36 Thirteen cases of TB were noted in the Abbott Pharmaceutical and FDA data for adalimumab; of these 8 occurred during phase I–II trials involving 524 rheumatoid arthritis patients, giving a rate of 2% in these patients but high doses of adalimumab had been used.36 TB screening and dose restriction were then instituted following which a further five cases occurred in the next 1900 patients with rheumatoid arthritis giving a reduced rate of 0.3%.28, 37–39 A recent analysis of a rheumatoid arthritis safety database with data on 10 050 patients exposed to adalimumab up to April 2005 noted event rates for TB prescreening of one per 100 patient years falling to 0.33 and 0.08 in Europe and North America respectively postscreening.40 The CHARM trial involving over 800 patients with Crohn’s disease noted 2 cases of TB in patients treated with adalimumab.41 Data regarding the newest anti-TNF-alpha antibody, certolizumab, are limited, but are derived from the Crohn’s patient population. The first two trials involving 384 patients did not report any cases of TB13, 14, but in the PRECiSE 2 trial involving 668 patients one case of pulmonary TB occurred.15

Table 1.   Tuberculosis (TB) rates in patients receiving anti-tumour necrosis factor (TNF)-alpha biologicals, background rates in control populations and nature of disease
Name of anti-TNF-alpha agentReferencesTB rate in treated patientsData sourceDates Background rate (rate, population ± source, dates)Time to diseasePercentage extrapulmonary (E) + disseminated (D)
  1. NDB, National Data Bank for Rheumatic Diseases; SIR, Swedish Inpatient Register; FDA, US Food and Drug Administration; RhA, rheumatoid arthritis; CBER, Center for Biologics Evaluation and Research; AERS, Adverse Event Reporting System; BIOBADASER, Spanish Society of Rheumatology Database; RR, relative risk.

Infliximab19144/100 000 patientsFDA AERS1998–20026/100 000
General population US 2001
40-day
median
No data
2524/100 000 patientsFDA AERS1998–20016/100 000
RhA pts US 2001
12-week
median
E 56
D 24
2762/100 000 patientsNDB1998–1999
2000–2002
6/100 000
NDB RhA pts 1998–1999
No dataE 75
D 0
291893/100 000 patients (2000)
1113/100 000 patients (2001)
BIOBADASER2000–200195/100 000
EMECAR RhA pts 1990–2000
3-month
mean
E 65
D 29
30145/100 000 patient years SIR1999–2001RR compared with RhA pts (who were noted to have a RR of 2 compared with general population) is 48-month medianE 33 (Infliximab+ D 13 Etanercept)
320/500 patientsMayo clinic1998–2002N/AN/AN/A
330/2850 patientsTREAT registry2002–2003N/AN/AN/A
Etanercept1935/100 000 patientsFDAAERS1998–20026/100 000
General population US 2001
236-day
median
No data
3080/100 000 patient yearsSIR1999–2001RR compared with RhA population is 15-month medianE 33 (Infliximab +D 13 Etanercept)
3510/100 000 patient yearsFDA AERS US1998–20026/100 000
RhA pts US 2001
12-month
median
E 54
D 12
370/3284 patientsCBERUp to Aug 2000None givenN/AN/A
Adalimumab28
36
39
13 cases: 8 in 524 pts (2%) in phase I–II (doses supra-therapeutic)
5 in next 1900 pts (0.3%)
Abbott PharmaceuticalsUp to 2002None givenMost in first 3–8 monthsE 27
D no data
412/800 patientsCHARM trial2003–2005None given9 monthsE 0
D 0
Certolizumab130/92 patientsMulticentre trialSep 2001–Apr 2002None givenN/AN/A
140/292 patientsMulticentre trialFeb2001–Mar 2002None givenN/AN/A
150/668 patientsMulticentre trialData not availableNone givenN/AN/A

It should be remembered that corticosteroid therapy is also associated with reactivation of TB. A case–control study in 526 patients with systemic lupus erythematosus in Hong Kong showed an odds ratio of 5.34 for the association between steroid therapy and TB.42 A recent analysis of IBD patients from the pre-infliximab era has demonstrated an increased predisposition for tuberculosis with an OR of 2.36 (95% CI: 1.17–4.74) compared with control subjects.43. The risk appears to be limited, if corticosteroid dosage and duration are minimized.28, 42–45. A smaller case–control study in rheumatoid arthritis patients did not, however, find any significant difference between TB cases and controls in exposure to steroids and also noted no increased risk of TB in patients on immunomodulators such as azathioprine and methotrexate44. There are no data assessing the impact of thiopurine therapy on risk of TB in patients also receiving anti-TNF therapy but two trials have assessed the combination of methotrexate with infliximab in rheumatoid patients. In one study in 428 patients the risk of serious infection, including but not exclusively tuberculosis, was similar for methotrexate alone as for the combination of infliximab with methotrexate46. However, in a larger trial involving 728 patients, an increased rate of TB was observed in patients on high dose (10 mg/kg) but not on low-dose (3 mg/kg) infliximab in combination with methotrexate.47

Mechanisms for tuberculosis reactivation with anti-tumour necrosis factor-alpha treatment

Tumour necrosis factor-alpha is a pro-inflammatory cytokine that exists both in membrane bound and in soluble forms, its action occurring as a result of binding to the TNF receptors p55 and p75.18

Murine models have helped elucidate the role of TNF-alpha in the immune response to Mycobacterium TB. TNF-alpha is important in recruiting inflammatory cells to sites of infection by inducing the production of chemokines and vascular adhesion molecules in macrophages and T cells.48 In TNF-alpha deficient mice recruitment of inflammatory cells is delayed and, once recruited, leucocytes fail to form organized granulomas for the containment of infection.49 Furthermore, once granulomas have formed, administration of anti-TNF-alpha in animal models can result in their regression50, 51 enabling reactivation of latent TB.

Tumour necrosis factor-alpha enhances the phagocytic and bactericidal abilities of macrophages via reactive nitrogen intermediate dependent and independent pathways, effects which are synergized with Interferon-gamma.48, 52 Logarithmic growth of intracellular bacteria (including mycobacteria as well as listeria and salmonella) was observed in TNF-alpha knockout mice until TNF-alpha was administered enabling intracellular killing.52, 53 Mice subjected to TNF-alpha inhibition by monoclonal antibody administration fail to produce reactive nitrogen species needed for intracellular killing.54 TNF-alpha inhibition also affects CD4 cell activity; in whole blood cultures, the proportion of TB-responsive T cells was reduced by administration of both infliximab and adalimumab as was antigen-induced interferon gamma production.55, 56 However, there is also some evidence that TNF-alpha has some anti-inflammatory effects that prevent over-activation of the immune system in response to TB.51

Screening tests for tuberculosis

History

Treatment with anti-TNF-alpha agents is only one of multiple risk factors that predispose to the development of TB. There is marked geographical variation in the incidence of TB raising the risk of development of the disease in immigrants from high risk areas.57, 58 Additionally, epidemiological studies have demonstrated increased risk of developing TB in institutionalized subject, those with a previous history of exposure to TB and an association with conditions such as HIV infection, chronic renal failure and transplantation. Thus clinical history provides a means of risk factor profiling for the presence of latent TB infection but while this allows identification of high risk subjects, lack of significant risk factors for latent infection does not entirely preclude its presence.59

Tuberculin skin test (TST)

The TST was developed in 1910 using injection of purified protein derivative (PPD) to induce a cutaneous hypersensitivity reaction in patients with TB. PPD is a bacteria-free filtrate containing over 200 antigens many of which are shared with the Bacille-Calmette-Guerin (BCG) vaccine. As a result, TST has low specificity in populations of low TB prevalence but high BCG usage60 and BCG vaccination can result in a falsely positive TST for up to 15 years postvaccination.22 Furthermore, falsely positive TSTs can occur following repeated testing.22

TST also has a low sensitivity, being particularly poor at detecting latent TB in high risk immunocompromised groups. Delayed hypersensitivity reactions are often suppressed in patients with HIV, undergoing dialysis, or receiving immunosuppressive therapy as most IBD patients undergoing infliximab therapy would be.22, 61 Mow et al demonstrated that in 82 patients with IBD undergoing TST, none had positive results and 71% failed to have positive skin tests to control antigens, supporting reports of high anergy rates in this patient population. Furthermore the investigators also noted that 83% of patients receiving corticosteroids or immunosuppressants (excluding infliximab) were anergic as compared with 43% of patients not receiving immunosuppressants.61 Similar results have been reported in patients with rheumatoid arthritis with 71% of rheumatoid arthritis vs. 26% of control subjects found to have negative TSTs.62 Accordingly the American Thoracic Society (ATS)63 guidelines for TST suggest that a lower induration cut-off of over 5 mm should be considered positive in patients receiving immunosuppressive therapy. The British Thoracic Society (BTS) guidelines, however, do not recommend TST in patients receiving immunosuppression.64, 65

Chest radiograph (CXR)

As a screening tool for active TB, CXR has a sensitivity of 59–82% and a specificity of 52–63%, both figures being markedly reduced in patients with HIV and other forms of immunocompromise.58 Furthermore, CXRs only demonstrate abnormality in 10–20% of patients with latent TB infection and have therefore been demonstrated not to be cost effective as a primary screening tool. However, given that patients with latent TB who demonstrate abnormalities on CXR are more likely to reactivate disease, this may provide useful supplemental information in addition to TST in screening.58

Gamma interferon-based assays – a useful addition?

Given the shortcomings of TST, attention has recently been focused on whole blood interferon gamma assays to detect TB infection. These tests use proteins encoded by Mycobacterium TB DNA, which are major targets for T cells secreting interferon gamma. They are, therefore, more specific for Mycobacterium TB being absent in most non-TB mycobacteria and the BCG vaccine. The two tests currently available are Quantiferon-TB Gold, using whole blood ELISA and T-Spot.TB using an enzyme linked immunospot assay (ELISpot). Because they produce a clear quantitative readout, these tests are not subject to operator reading bias. Furthermore, they have internal controls using non-specific stimulators of interferon production, thus producing indeterminate rather than falsely negative results, if control samples fail to produce a reaction. Results are available within a day and do not require return visits but they do require trained skilled staff in laboratories with specialized equipment and the blood needs to be processed within a set time frame, usually 12 h.22

In immunocompetent individuals, the efficacy of the tests in detecting latent TB infection has been assessed in contact tracing studies using the degree of exposure as a surrogate for risk of latent TB. Large trials involving both tests have demonstrated improved correlation with exposure on comparison with TST, but both tests were noted to have poor sensitivity (42–51%) in patients with markedly positive TST of more than 15-mm induration.60, 66 Specificity of the interferon-gamma assays has been assessed by studying BCG-vaccinated subjects with a low risk of latent TB infection. Here, both assays demonstrated higher specificity than TST ranging from 96–100%.60, 67

T-Spot.TB has also shown promise in immunocompromised patients, having been found to be more sensitive than TST in HIV patients, immunosuppressed haematological patients and young children in Africa with HIV infection and malnutrition.60, 68–71 Similar studies have not been performed with Quantiferon-TB Gold, but the rate of indeterminate results does appear to increase with this test in patients receiving immunosuppressive therapies or with HIV infection72, 73. However, case reports suggest Quantiferon-TB Gold provides a greater sensitivity for latent TB infection than TST in patients with rheumatoid arthritis and polymyositis.74, 75 A cost analysis by the National Institute of Clinical Excellence has suggested that for diagnosis of latent TB, a two stage test strategy with an initial TST followed in positive cases by interferon gamma assays provides cost-effective screening at £26 000 per quality-adjusted life-year (QALY). While the cost of interferon gamma assays used alone was estimated at over £150 000 per QALY gained, poor performance of TST in Crohn’s disease might make single testing with interferon gamma assays more cost effective in this group.76

Current recommendations

Recommendations by the BTS, CDC, ATS and the European Agency for the Evaluation of Medicinal Products all support screening prior to initiation of anti-TNF-alpha therapy (Table 2). In all cases, a detailed history and examination to establish risk of latent TB infection is recommended.57, 63–65 The American guidelines suggest this be combined with a TST although clinicians are urged to be wary of false negative results and thus use a lower positive reading of ≥5-mm duration. In the setting of immunosuppression, the British guidelines, however, do not include TST but rely on history and examination together with CXR to evaluate risk for current or previous TB. In the setting of immunosuppression with a normal CXR, a risk assessment is made taking into account age, ethnicity, place of birth and duration of UK residence to determine whether chemoprophylaxis would be advisable (see Table 3).64, 65 In Crohn’s disease, where anergy is common both as a consequence of the disease and of immunosuppression, further studies are needed to determine whether the combination of history and CXR together with interferon gamma assays may provide a more effective screening. Whether screening ought to be repeated at regular intervals to limit the risk of TB still further is also currently unclear.

Table 2.   Current guidelines for tuberculosis (TB) screening in patients about to receive anti-tumour necrosis factor (TNF)-alpha therapy
SourceHistory +ExamCXRTSTOtherConsider chemoprophylaxis or avoiding anti-TNF-alphaRecommended chemoprophylaxisLength
  1. BTS, British Thoracic Society; CDC, Centers for Disease Control; ATS, American Thoracic Society; EMEA, European Agency for the Evaluation of Medicinal Products.

BTS 53, 54YesYesYes if CXR normal and no immunosuppressionIf normal CXR and immunosuppression do risk-benefit calculation with history without TST*Abnormal CXR
*History inadequately treated TB
*Risk assess for treatment if TST≥5 with no Bacille-Calmette- Guerin (BCG), ≥15 mm if previous BCG
*Risk assess if normal CXR +on immunosuppression: treat if risk-benefit favours chemoprophylaxis
Isoniazid
Rifampicin +isoniazid
6 months
3 months
CDC+ATS
51, 52
YesYesYes/TST ≥5 mmIsoniazid
Rifampicin
6–9 months
4 months
EMEA
78
YesYesYes/As per local recommendationsAs per local recommendationsAs per local recommendations
Table 3.   Tuberculosis risk calculation table
 Annual risk of tuberculosis (TB) disease/100 000TB risk adjusted X5 for anti-tumour necrosis factor effect Risk of prophylaxis (side-effects)/100 000 Risk/benefit conclusion
  1. Adapted from Ref.64.

  2. Risk of prophylaxis is based on isoniazid as single agent.

White
Age 55–74
UK born
735278Observation
Indian subcontinent-born
Age > 35
In UK 3 years
5932965278Prophylaxis
Black African
Age 35–54
168840278Prophylaxis
Other ethnic
Age 35+
In UK >35 years
39195278Observation

Recommended treatment regimes for patients considered at high risk for latent TB as a result of screening vary from isoniazid alone for 6–9 months to rifampicin alone for 4 months to both drugs combined for three months. Debate continues as to whether chemoprophylaxis has to be completed entirely or only partially before anti-TNF-alpha agents can reasonably be commenced and the relative risks of TB activation and continued Crohn’s disease activity may have to be individually assessed for each patient.

Efficacy of current screening protocols

Case reports noting TB infection in patients who have undergone negative screening prior to infliximab commencement have raised concerns as to the efficacy of current screening methods.77 However, there is considerable evidence to support their efficacy. A study in Spain using the BIOBADASER registry noted that only 2 out of 34 cases of TB occurred after the introduction of screening (involving TST and CXR prior to infliximab commencement and 9-month isoniazid therapy in positive cases), giving a rate decrease of 78%.78 Similarly, Wolfe and colleagues examining patients having infliximab therapy in the US between 2000–2002, found four cases of TB none of which occurred in patients who had undergone pre-treatment TST or chemoprophylaxis.18, 27, 28 Perez et al.79 reviewed data from patients receiving adalimumab in clinical trials before and after the introduction of screening (TST and CXR) and chemoprophylaxis with isoniazid and calculated a 90% rate reduction of TB reactivation following introduction of screening.

Efficacy of chemoprophylaxis in patients who are positive on screening

Chemoprophylaxis is only moderately effective.78, 80, 81 Patients with latent TB infection on average have less than 100 000 tubercle bacilli.82 Studies in both HIV negative and positive patients have shown that isoniazid therapy for 6 and 12 months in patients with latent TB is superior to placebo and maximal benefit can be obtained with 9-month therapy.83, 84 However, current evidence indicates that even 9-month therapy with isoniazid only reduces the rate of developing TB by about 70%.78 Sichletidis et al.80 studied 613 patients receiving anti-TNF-alpha therapy for connective tissue diseases from 2000–2004. Patients underwent screening by TST and CXR and were prescribed chemoprophylaxis in the event of positive screening tests; anti-TNF-alpha therapy was commenced following 2 months of prophylactic therapy. Forty five patients had positive screening test results, but only 36 underwent adequate chemoprophylaxis; 3 patients stopped because of hepatotoxicity and six patients took inadequate courses or refused treatment. Eleven patients developed TB after anti-TNF-alpha therapy; only one of these patients had negative screening tests and this patient developed TB 12 months after commencement of therapy. Of the remaining 10 patients, one refused chemoprophylaxis and two had inadequate courses. Thus out of 36 who received adequate chemoprophylaxis 7(19%) developed TB.

Effectiveness of chemoprophylaxis is limited not only by the efficacy of the drug but also by adherence to therapy. Four months treatment with rifampicin has been evaluated as an alternative to 9-month isoniazid therapy and shown to be associated with improved compliance.85 However, the efficacy of rifampicin in comparison with isoniazid is yet to be formally assessed in patients with IBD undergoing anti-TNF-alpha treatment. It is also unclear when anti-TNF-alpha treatment may safely be started in patients who have received chemoprophylaxis. It is usually recommended that anti-TNF-alpha treatment is withheld until at least one month but preferably until a complete course of chemoprophylaxis has been given but as yet no studies have evaluated this objectively.82, 86 Patients receiving anti-TNF-alpha therapy after chemoprophylaxis for suspected latent TB need to realize that this does not fully protect against development of active disease.78, 80, 86

Conclusion

TNF-alpha antagonists have revolutionized the treatment of IBD; however, their use has been accompanied by the risk of reactivation of latent TB infection, often in extrapulmonary sites and not infrequently leading to disseminated and sometimes fatal disease. The risk of TB reactivation is common to all anti-TNF-alpha therapies, although it is most evident with the anti-TNF-alpha antibodies. Animal models suggest that reactivation of TB occurs as a result of impaired host immune responses to the mycobacteria, specifically relating to impaired granuloma formation and immune cell function. It is widely recommended that patients about to undergo anti-TNF-alpha therapy should first be screened to assess their risk for latent TB and to exclude active infection. However, the sensitivity and specificity of TST in patients with IBD are limited by frequent presence of anergy and CXR has very poor sensitivity for latent TB. Testing based on interferon gamma assays may improve the efficacy of screening and hence enhance the safety of anti-TNF-alpha therapy, but more studies are necessary to evaluate this. Whilst current screening with a careful history coupled with TST and CXR does not confer full protection, it appears to reduce the risk of reactivation of TB infection by up to 90%. Clinicians need to remain vigilant for reactivation of TB in patients receiving anti-TNF-alpha therapy.

Acknowledgements

Declaration of personal and funding interests: Prof Rhodes is a member of advisory boards for Procter and Gamble, Falk, UCB, Genentech and, with the University of Liverpool and Provexis UK, holds a patent for use of a soluble fibre preparation as maintenance therapy for Crohn's disease. Dr Theis has no conflicts of interest.

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