Rheumatology Advance Access originally published online on October 27, 2007
Rheumatology 2007 46(12):1864-1865; doi:10.1093/rheumatology/kem256
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Comment on: Use of the QuantiFERON-TB® Gold test as part of a screening programme in patients with RA under consideration for treatment with anti-TNF-
agents: the Newcastle (UK) experience: reply
1Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH,
2Musculoskeletal Unit, Freeman Hospital, High Heaton, Newcastle upon Tyne NE7 7DN, UK
Correspondence to: A. Pratt, Floor 4, Catherine Cookson Building, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. E-mail: arthur.pratt{at}ncl.ac.uk
SIR, We are grateful to Dr Kaushik and co-authors [1] for their cautionary comments regarding the interpretation of data arising from our audit [2]. We agree wholeheartedly that further and more in-depth studies are needed in this area to properly establish the precise role of IFN
-based tests in screening for Latent tuberculosis infection (LTBI) amongst RA patients due to start anti-TNF-
therapy, with a particular emphasis on cost-effectiveness (which, in our concluding remarks, we clearly stated was a matter of potential, not fact). However, we are of the opinion that the shortcomings of the QuantiFERON-TB® Gold test (QTG) summarized by Kaushik et al. [1] are surmountable, whereas some of those of the tuberculin skin test (TST)—in particular, its recognized lack of specificity amongst bacille Calmette-Guérin (BCG)-exposed individuals in low-prevalence populations [3]—are not. Kaushik et al. [1] contest the validity of this latter shortcoming, but we would question their reliance in this point on a study of an epidemiologically rather distinct population from Guinea-Bissau which addressed the separate issue of tuberculosis (TB) contact-tracing [4]. Furthermore, we feel that before describing the tuberculin skin test (TST) as ‘free’, the cost of professional time involved in its administration and interpretation over two patient visits should be taken into account. In accordance with the now familiar British Thoracic Society (BTS) guidelines [5], therefore, which conclude that the TST will be unhelpful in screening patients who have been on immunosuppressive therapy (including corticosteroids and methotrexate), we chose not to employ that test as a screening tool in our patient cohort. We would, however, highlight a recent report [6] that did make comparison between TST and QTG in predominately Caucasian patients with rheumatic conditions, in which prior BCG vaccination was shown to affect TST but not QTG outcome.
The risk stratification process, advocated for use in immunosuppressed patients by the BTS guidelines [5] and referred to by our correspondents, which balances an estimate for age- and ethnicity-adjusted annual risk of TB in anti-TNF--treated patients with the hepatic risks of chemoprophylaxis, was published some time after recruitment for our audit commenced. We are grateful for the opportunity to mention that when applied retrospectively, these criteria would have identified just one (female, Asian) patient in our cohort as warranting chemoprophylaxis; this patient was QTG-negative and had no complications after 1 yr of etanercept treatment. It is of course not possible to say with certainty whether any of the four patients ultimately treated with anti-TNF- agents who had positive QTG tests, all of whom underwent respiratory physician-guided chemoprophylaxis, did indeed represent ‘true positives’ with respect to LTBI.
Dr Kaushik and co-authors [1] doubt that the QTG test has a robust negative predictive value in our RA patient population. Specifically, they wonder whether some of the 83% of patients who were QTG-negative might have simply mounted inadequate T-cell responses secondary to immunocompromise. In such a scenario, a given sample's incubation with mitogen in a positive control reaction would, because of T-cell hyporesponsiveness, fail to induce IFN secretion above the threshold necessary for interpretability, and the test result would by definition be indeterminate rather than negative [7]. This particular mechanism for the derivation of false negatives is thus neatly circumvented, although it is true that others may not be. In the absence of a satisfactory gold standard LTBI test, assessment of the negative predictive value of the QTG test is therefore ultimately reliant on long-term follow-up, and although we feel that our follow-up period (average 
18 months) should have been sufficient in most cases (particularly amongst infliximab-treated patients in whom LTBI reactivations occur preferentially within 3 months of treatment initiation [8]), we concede that a longer period of follow-up amongst a larger population size would be desirable: this is of course an ongoing concern.
Kaushik et al. [1] object to the ‘many’ (10% of our cohort) individuals whose QTG test result was indeterminate and hence uninformative, and in whom a combination of careful history-taking (including TB contact exposure), clinical examination and radiological evaluation was the sole decision-making tool—a process referred to by our correspondents as qualified guesswork. We would draw attention to the considerably higher proportion (72%) of our ‘immunocompromised’ patient population who were known to have had prior exposure to BCG, and in whom interpretation of a positive TST would have been difficult, and point out once again that our rate of QTG indeterminate test results is comparable with that seen in non-immunocompromised cohorts elsewhere [9], suggesting that the informativeness of this test in the clinical context described is not adversely affected by T-cell hyporesponsiveness, a finding corroborated independently (and perhaps yet more convincingly) by others [6].
We thank our correspondents once more for their constructive remarks, but stand by our assertion that use of the QTG test for this purpose is feasible, potentially cost-effective and not apparently affected by increased rates of uninformative results in our clinical setting.
Disclosure statement: K. N. has received honoraria from Abbott Laboratories, Schering Plough Ltd and Wyeth Biotechnology Let, and has received a research grant (March 2003 to March 2005) from Schering Plough Ltd. A. P. has been funded to attend a conference by Schering Plough Ltd. L. K. has participated in clinical trials by Abbot Laboratories and Wyeth Pharmaceuticals.
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- Kavshik VV, Ambalavanan S, Binymin K. Comment on: Use of QuantiFERON TB Gold test as part of a screening programme in patients with RA under consideration for treatment with anti-TNF- agents: the Newcastle (UK) experience. Rheumatology (2007) 46:1863–4.
[Free Full Text] - Pratt A, Nichol K, Kay L. Use of the QuantiFERON TB Gold test as part of a screening programme in patients with RA under consideration for treatment with anti-TNF- agents: the Newcastle (UK) experience. Rheumatology (2007) 46:1035–6.
[Free Full Text] - Richeldi L. An update on the diagnosis of tuberculosis infection. Am J Resp Crit Care Med (2006) 174:736–42.
[Abstract/Free Full Text] - Gustafson P, Lisse I, Gomes V, et al. Risk factors for positive tuberculin skin test in Guinea-Bissau. Epidemiology (2007) 18:340–7.[CrossRef][Web of Science][Medline]
- Ormerod LP, Milburn HJ, Gillespie J, Ledingham J, Rampton D. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax (2005) 60:800–5.
[Abstract/Free Full Text] - Matulis G, Juni P, Villiger PM, Gadola SD. Detection of latent tuberculosis in immunosuppressed patients with autoimmune diseases – performance of Mycobacterium tuberculosis antigen specific IFN-gamma assay. Ann Rheum Dis (online) (2007) July;20. doi:10.1136/ard.2007.070789.
- QuantiFERON TB-Gold In-TubeTM Package Insert. http://www.cellestis.com/IRM/Company/ShowPage.aspx?CPID=1255.
- Wallis RS, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumour necrosis factor blockade: correction. Clin Infect Dis (2004) 39:1254–5.[CrossRef][Web of Science][Medline]
- Ferrara G, Losi M, D’Amico R, et al. Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study. Lancet (2006) 367:1328–34.[CrossRef][Web of Science][Medline]
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