Expert Opinion on Biological Therapy
ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: http://www.tandfonline.com/loi/iebt20
Usefulness of QuantiFERON®-TB Gold test in psoriatic patients under treatment with tumour necrosis factor blockers Rosita Saraceno MD, Francesca Specchio MD, Andrea Chiricozzi MD, Loredana Sarmati MD, Massimo Amicosante MD, Maria Sole Chimenti MD & Sergio Chimenti MD To cite this article: Rosita Saraceno MD, Francesca Specchio MD, Andrea Chiricozzi MD, Loredana Sarmati MD, Massimo Amicosante MD, Maria Sole Chimenti MD & Sergio Chimenti MD (2014) Usefulness of QuantiFERON®-TB Gold test in psoriatic patients under treatment with tumour necrosis factor blockers, Expert Opinion on Biological Therapy, 14:2, 151-156, DOI: 10.1517/14712598.2014.860441 To link to this article: http://dx.doi.org/10.1517/14712598.2014.860441
Published online: 05 Dec 2013.
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Original Research
1.
Introduction
2.
Patients and methods
3.
Results
4.
Discussion
5.
Conclusion
Usefulness of QuantiFERON-TB Gold test in psoriatic patients under treatment with tumour necrosis factor blockers Rosita Saraceno†, Francesca Specchio, Andrea Chiricozzi, Loredana Sarmati, Massimo Amicosante, Maria Sole Chimenti & Sergio Chimenti †
University of Rome Tor Vergata, Division of Dermatology, Department of Internal Medicine, Rome, Italy
Objective: Infliximab is a human/mouse chimeric anti-tumour necrosis factor (TNF)-a antibody that is effective in the management of psoriasis. Anti-TNF treatments may reactivate latent tuberculosis infection (LTBI); therefore, screening for LTBI is mandatory before starting any anti-TNF-a therapy. The aim of this study is to evaluate the usefulness of the QuantiFERON-TB Gold (QFT-G) test in psoriatic patients under treatment with infliximab. Research design and methods: A retrospective study had been performed on patients affected by psoriasis who had been treated with infliximab from 2003 to 2012 at a single centre. Main outcomes measures: QFT-G was tested by a standard TB enzyme-linked immunosorbent assay, based on detection of interferon-g release from sensitized leucocytes exposed to the synthetic Mycobacterium tuberculosis antigens at baseline and every 6 months until the end of treatment. Results: A total of 140 patients were included. At baseline, 7 QFT-G tests were positive and 133 tests were negative. Of the 133 patients, 11 (8%) who were negative at baseline became QFT-G test positive during treatment. Of those 11 patients, 5 had a reversion during treatment. Of the 133 patients, 122 (92%) who were negative at baseline remained negative. Conclusions: It was found that the development of positive QFT-G tests, observed in 8% treated with infliximab, was not associated with pulmonary or extra-pulmonary tuberculosis. Keywords: anti-tumour necrosis factor-a blockers, infliximab, psoriasis, QuantiFERON-TB Gold tests, tumour necrosis factor-a Expert Opin. Biol. Ther. (2014) 14(2):151-156
1.
Introduction
Psoriasis is a chronic, inflammatory and debilitating disease of the skin, nails and joints, with an acknowledged and complex pathogenesis [1]. Treatments of moderateto-severe psoriasis include methotrexate, cyclosporine, fumarates, acitretin and biologics [2]. The latter comprises anti-tumour necrosis factor (TNF)-a agents largely used in the treatment of Crohn’s disease, rheumatoid arthritis (RA) and seronegative spondyloarthropathies. The TNF-a inhibitors such as infliximab, etanercept and adalimumab have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of psoriasis [3]. Infliximab, a human/ mouse chimeric anti-TNF-a antibody, is a highly effective treatment for both plaque-type psoriasis and psoriatic arthritis [4,5]. Treatment with all the anti-TNF-a agents increases the risk of latent tuberculosis infection (LTBI) reactivation [6], and there are few post-marketing reports on 10.1517/14712598.2014.860441 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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the development of both active tuberculosis (TB) and LTBI after initiation of anti-TNF-a therapy in psoriatic patients [7-10]. Recent Centers for Disease Control and Prevention recommendations suggest that tuberculin skin test (TST) and Interferon (IFN)-gamma release assay tests (IGRAs) (QuantiFERON-TB Gold [QFT-G], QuantiFERON-TB Gold In-Tube test and T-Spot) should be used as aids in diagnosing of M. tuberculosis infection [11]. Owing to possible false interpretation of the TST, especially in cases of immunosuppression, in Bacillus Calmette--Gue´rin (BCG)-vaccinated patients and in patients who have already started anti-TNF therapy, IGRAs may have an advantage over TST in terms of both sensitivity and specificity [12,13]. Information about the use of IGRAs in immunocompromised hosts has been provided by a growing number of reports; however, some limitations about the reproducibility of the test have been described [12-16]. Moreover, recently, the use of anti-TNF-a has been associated with the induction of positive QFT-G test in absence of a clinical correlations [12-17]. The aim of this study was to determine the performance of QFT-G test conversions and reversions in psoriatic patients under treatment with infliximab.
2.
Patients and methods
A retrospective review of the clinic database at the Department of Dermatology of the University of Rome Tor Vergata using the term ‘infliximab’ was undertaken. Using this database-generated list, all charts were reviewed, identifying case subjects seen in the day care unit and in the psoriasis clinic from 2003 (at the initiation of the database) to 2011. The baseline characteristics of age, sex, psoriasis phenotype, onset of the disease, comorbidities, previous systemic treatments for psoriasis and any concurrent medications were obtained. Exclusion criteria were subjects who were never treated with infliximab, the treatment period with infliximab was < 12 months, or the baseline QFT-G test was unavailable before commencing infliximab, or concurrent immunosuppressive drugs were prescribed. All patients treated with infliximab were unresponsive or contraindicated to at least two systemic conventional therapies. Patients with infectious disease, active or latent neoplastic disease (in the past 5 years), severe heart failure or demyelinating disorders were also excluded. All patients received infliximab as a continuous treatment and it was administered intravenously at weeks 0, 2, 6 and then every 8 weeks. The BCG vaccination status was reported either in patient medical history or assumed by the presence of vaccination scars. Clinical data were recorded and a questionnaire was administered to evaluate the risk of TB exposure [18]. 152
To rule out LTBI, IFN-g production was determined using QFT-G. The test was performed before starting the biological treatment (baseline) and every 6 months to monitor possible seroconversion. Peripheral blood was collected into three different tubes: the first containing no antigen (negative control or nil), the second containing TB-specific antigens and the third containing phytohaemagglutinin (mitogen or positive control). Blood samples were processed according to the manufacturer’s protocol (Cellestis: QuantiFERON-TB Gold package insert http://www.cellestis.com/IRM/Company/ ShowPage.aspx?CPID=1255). Results were evaluated according to the criteria established by the manufacturer, considering a result as positive if the IFN-g response of TB antigen minus nil was ‡ 0.35 IU/ml. Conversion was defined as a baseline IFN-g concentration < 0.35 IU/ml and a follow-up IFN-g concentration ‡ 0.35 IU/ml. Reversion was defined vice versa. All IFN-g release assays were retested at the same centre as the baseline IGRA. Analyses were carried out by the accredited Clinical Chemical Laboratories of the ‘Tor Vergata’ Polyclinic of Rome, Italy. Mantoux test was performed in positive QFT-G patients. Active TB was ruled out by chest X-ray and/or computed tomography (HRCT) in all participants with positive baseline QFT-G results and in those with conversions. TST was performed according to Mantoux method by injecting 5 UI of the antigen subcutaneously. An induration > 5 mm appearing after 48 h was considered positive. We used the cut off of 5 mm to define a positive tuberculin reaction because we considered our population as a population of immunosuppressed people as they were treated with immunosuppressive drugs [19]. Since, to date, there are not shared guidelines on the prophylaxis and timing of initiation of anti-TNF-a treatment, in our population, patients who showed positivity to QFT-G and/or TST underwent chemoprophylaxis with isoniazid 300 mg/day for 9 months [20-22]. Data for each of the study outcome variables were checked for normality of distribution using the Kolmogorov--Smirnov test. Quantitative variables were expressed as mean ± SD. Categorical variables were presented as numbers (%). The concordance level between QFT and TST assays was assessed with chi-squared tests and the strength of agreement was examined using Cohen’s kappa. Kappa values > 0.75 represented excellent agreement, values between 0.40 and 0.75 represented fair to good agreement and values < 0.40 represented poor agreement beyond chance.
3.
Results
A total of 169 patients treated with infliximab during the study period were analyzed (Table 1). Of the 140 patients that met the study criteria for inclusion, 93 were male and 47 were female. The mean age was 52 years (± 14), with a range of 23 to 84 years. Of the 140 subjects, 72 (52%) and 68 (48%)
Expert Opin. Biol. Ther. (2014) 14(2)
Usefulness of QFT-G test in psoriatic patients under treatment with TNF blockers
Table 1. Demographical data and clinical features of the study population.
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Number of patients Mean age (years ± SD) Male/female (n) Onset of the disease (years ± SD) Plaque-type psoriasis (n, %) Psoriatic arthritis (n, %) Previous immunosuppressive systemic therapies Mean number of previous immunosuppressive systemic therapies Mean number of previous biological agents TB risk Chest X-ray at baseline and during treatment
140 52 (±14) 93/47 28 (±15) 72 (52%) 68 (48%) 137/140 (97%) 2.5 0.4 31/140 (22%) 140/140 (100%)
Table 2. Agreement rates between TST and QFT-Gold assays at baseline in the study population.
TST
TB GOLD +
-
+
4
6
-
3
127
Patients agreement between the two tests was moderate according to Cohen’s kappa score (k = 0.4).
subjects had plaque-type psoriasis and psoriatic arthritis, respectively. The mean period of treatment was 3 years. The main risk factor for TB in the study population was the condition of immunosuppression secondary to prolonged immunosuppressive treatments. Only three patients were never treated with conventional immunosuppressive therapies because of concomitant comorbidities. None of the 140 subjects were HIV-positive, malnourished or were previously exposed to patients with active TB. Additional risk factors for TB infection were recorded in 31 of 140 patients: smoking more than 20 cigarettes a day (n = 11); diabetes mellitus (n = 13); travelling to countries that have high rates of TB (n = 4) and professional exposure (n = 5). Of the 169 patients, 29 were excluded from the study for the following reasons: i) had positive baseline QFT-G (n = 7); ii) were treated in association with methotrexate (n = 2); iii) did not have baseline or routine QFT-G available (n = 9); iv) were lost to follow up (two patients continued treatment in a different centre); and v) the duration of infliximab treatment was < 12 months (n = 9). In the latter group, five patients discontinued the therapy due to lack of efficacy and four patients discontinued for adverse events. Reasons for discontinuation were allergic reaction (urticaria and oedema) during the infusion (n = 1), pulmonary infection (n = 2) or pregnancy (n = 1). At baseline, 7 patients were QFT-G positive and 133 patients were negative. Four QFT-G positive patients
were also TST positive (Table 2). Patients agreement between the two tests was moderate according to Cohen’s kappa score (k = 0.4). The 7 patients who were QFT-G positive prior to starting infliximab underwent chest-X ray and/or HRCT to exclude active TB. Patients who were considered affected by LTBI began TB prophylaxis, according with the current recommendations [20-22]. In these patients, anti-TNF-a treatment was postponed until after 6 months of TB prophylaxis. Of the 133 patients, 11 (8%) patients who were negative at baseline became QFT-G positive during the study period. Of the 11 patients, 10 were men and the mean age was 51 years. None of the 11 patients had previously received the BCG vaccine. Of the 11 patients who became QFT-G positive, all had negative Mantoux tests except two patients: of those, one had positive Mantoux test of 10 mm diameter and one was lost to follow up. Patients who became QFT-G positive during the treatment withdrew from the anti-TNF-a therapy and began TB prophylaxis as reported below. The mean time of conversion was 40 months (mean value of QFTG = 3.7 IU/ml ± 5.17). Of those 11 patients, 5 had subsequent reversion to QFTG negative (see Figure 1). The mean period of reversion was 16 months. None of the 11 study subjects who turned QFT-G positive developed active TB within the observational period of > 3 years. A total of 122 patients who were QFT-G negative at the beginning remained stably QFT-G negative for the whole duration of infliximab treatment. 4.
Discussion
In this study we evaluated the use of IGRA in the serial testing of psoriatic patients under long-term treatment with infliximab. We observed a strong overall concordance between baseline and follow up in subjects with negative QFT-G. In contrast, in patients presenting a conversion during treatment, reversions occurred in 50% of the study subjects. In our study, 11 psoriatic patients developed QFT-G positivity during treatment with infliximab. Interestingly, 10 of the 11 patients who developed QFT-G conversion during infliximab treatment were men, thus suggesting a gender correlation. Moreover, we found that in the long-term treatment (> 3 years of follow up), the development of QFT-G positivity was not associated with a risk of TB reactivation. Similar to our findings, Garcovich et al. [23] have previously assessed, in a prospective study, the role of QFT in the diagnosis of LTBI during systemic anti-TNF-a treatment in psoriasis patients. They showed that single-test QFT-based screening strategy for LTBI was proven effective in reducing the incidence of false-positive LTBI cases and, thereby, in preventing unnecessary TB chemoprophylaxis. During 12 months of continuous anti-TNF-a treatment, the authors found that QFT conversions occurred in 10% (five cases) of the initial study population (n = 50) with three QFT/TST
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Figure 1. The graph shows longitudinal variations in IFN-g in 11 psoriatic patients treated with infliximab; five of those had subsequent reversion to QFT-G negative. The IFN-g response to M. tuberculosis-specific antigens was measured by QFT-G before and during treatment. The cut-off value for a positive result was 0.35 IU/ml. The reasons for treatment discontinuation were not related to the QFT-G results.
concordant cases after 6 months and two more QFT/TST discordant cases after 12 months of treatment. Isoniazid therapy was initiated for a 6-month-long course along with previous anti-TNF-a treatment. The authors suggested that a single-test QFT-based screening strategy for LTBI in psoriasis patients receiving continuous long-term anti-TNF-a treatment could reduce the incidence of false-positive LTBI cases, preventing unnecessary TB chemoprophylaxis. In contrast to the abovementioned research, our population was larger and was studied for a longer period. Moreover, we included only patients who were treated with infliximab, whereas Garcovich et al. included three patients who were treated with infliximab and the rest were treated with etanercept and adalimumab. The use and the reliability of TST as a tool for serial testing are limited by cross-reactivity due to i) BCG vaccination and ii) exposure to non-tuberculous mycobacteria, nonspecific variations and false positivity mimicked by koebnerization in the site of the antigen inoculation in psoriatic patients [12]. Moreover, TST shows low specificity in vaccinated subjects and lower sensitivity in immunosuppressed patients, compared to healthy subjects. For all these argumentations, in the latest years, QFT-G test has been preferred since the diagnostic accuracy in detecting LTBI is higher [16]. QFT-G test is an in vitro blood test measuring the production of IFN-g by T cells exposed to antigens highly specific for Mycobacterium tuberculosis. It seems to be unaffected by prior BCG vaccination and, thus, offers an increased specificity compared to TST [17]. QFT-G test detects levels of IFN-g, which it might be theoretically produced by both activated T cells, likely because of a concomitant TB infection, and 154
memory T cells, as pre-sensitized to TB antigens in vaccinated or previously exposed subjects. The development of QFT-G positivity during anti-TNF-a therapy is a well-known occurrence that has been reported in RA, spondyloarthritis, intestinal bowel disease and psoriasis [20]. Infliximab is highly effective in treating these conditions. It is an IgG1 murine-human anti-TNF-a antibody binding both soluble and transmembrane TNF-a [24]. Modulating the immune response, it may be associated with an increased risk of reactivation with infectious granulomatous pathogens, such as M. tuberculosis. Although not excessive, the risk of reactivation requires screening tests [6]. It is hard to explain how IGRA-negative subjects at the baseline might develop positivity to IGRA test while undergoing treatment with infliximab. It could be postulated that positivity to IGRA is considered a risk of reactivation of TB infection or it may be a sign of a de novo (new) infection contracted during therapy. However, longitudinal studies have revealed a considerable fluctuation in IFN-g responses to serial testing in TB patients or in TB-exposed healthcare workers [25-28]. These fluctuations might be attributed to limitations in the accuracy of IGRAs or to actual fluctuations in IFN-g levels in the same patient. Some increases in IFN-g levels might be attributed to new infection or to a boost following TST. Some decreases in IFN-g levels might be attributed to anti-mycobacterial treatment. However, for the most part, fluctuations in IFN-g levels among serially tested patients reported in longitudinal studies remain unexplained and nonspecific. The magnitude of these fluctuations can be of sufficient size to misinterpret the test in terms of conversion
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Usefulness of QFT-G test in psoriatic patients under treatment with TNF blockers
or reversion, especially when the IFN-g levels are near cut points dissecting positive and negative results. The correct meaning and evaluation of this laboratory data, therefore, remain unclear. In particular, this phenomenon in patients treated with anti-TNF-a drugs could be related to a possible interference between the anti-TNF-a activity and the immune response to TB infection. Three possible mechanisms could be hypothesized: i) it has been shown that infliximab interferes in regulatory T-cell (Treg) activity, reducing IL-10 synthesis [29]; it is likely that IFN-g production is modulated by Treg and thus, even a slight production might be detectable and test results as positive; ii) infliximab modulates the activity of T cells that bear transmembrane TNF-a, but quiescent memory T cells, previously sensitized to TB antigens, might be not affected by infliximab because antiTNF-a agents are immunomodulators and not immunosuppressants because immune pathways still remain operative (the reason why serious infections are not so common); iii) it is known that QFT-G is not affected by previous vaccination, but it is reasonable that memory T cells, whether they have been previously exposed to M. tuberculosis antigens, might become reactive performing the in vitro stimulation with TB gold quantiferon antigens. It has been demonstrated that infliximab induces apoptosis in activated, but not quiescent, T cells [30]. Is it likely that the fluctuation of QFT-G in patients treated with anti-TNF-a might represent just an activation of clonal T cells without a pathological meaning? And, if it is so, are we overtreating patients with useless and possibly toxic antitubercular prophylaxis? All these arguments lead us to carefully consider the Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Conclusion
Infliximab may reactivate LTBI and for this reason screening for LTBI is mandatory before starting therapy and during treatment. In our study, we observed 8% of development of positive QFT-G tests, and reversions occurred in about 50% of psoriatic patients during infliximab administration. However, since positivity was not associated with pulmonary or extrapulmonary TB, the QFT-G fluctuations might be attributed to limitations in the accuracy of IGRAs or to actual fluctuations in IFN-g levels in the same patient possibly induced by the anti-TNF-a interference to the immune response to TB test. Finally, even though the small study population and the IGRA test used represent a limitation of this study, the results allow us to hypothesize a low risk of progression to active TB in patients developing QFT-G conversion without any recent, certain and prolonged exposure. Therefore, before beginning TB prophylaxis in patients with QFT-G test conversion, the possibility of a false-positive IGRA result should be rule out by TST and radiological examinations.
Declaration of interest The authors have received speaker fees from MSD, the manufacturer of infliximab.
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Expert Opin. Biol. Ther. (2014) 14(2)
Affiliation
Rosita Saraceno†1 MD, Francesca Specchio1 MD, Andrea Chiricozzi1,5 MD, Loredana Sarmati2 MD, Massimo Amicosante4 MD, Maria Sole Chimenti3 MD & Sergio Chimenti1 MD † Author for correspondence 1 University of Rome Tor Vergata, Division of Dermatology, Department of Internal Medicine, Rome, Italy Tel: +390620902743; Fax: +390620902742; E-mail: [email protected] 2 University of Rome Tor Vergata, Division of Infectious Diseases, Department of Internal Medicine, Rome, Italy 3 University of Rome Tor Vergata, Division of Rheumatology, Department of Internal Medicine, Rome, Italy 4 University of Rome Tor Vergata, Department of Biomedicine and Prevention, Rome, Italy 5 The Rockefeller University, Laboratory for Investigative Dermatology, New York, NY, USA
ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: http://www.tandfonline.com/loi/iebt20
Usefulness of QuantiFERON®-TB Gold test in psoriatic patients under treatment with tumour necrosis factor blockers Rosita Saraceno MD, Francesca Specchio MD, Andrea Chiricozzi MD, Loredana Sarmati MD, Massimo Amicosante MD, Maria Sole Chimenti MD & Sergio Chimenti MD To cite this article: Rosita Saraceno MD, Francesca Specchio MD, Andrea Chiricozzi MD, Loredana Sarmati MD, Massimo Amicosante MD, Maria Sole Chimenti MD & Sergio Chimenti MD (2014) Usefulness of QuantiFERON®-TB Gold test in psoriatic patients under treatment with tumour necrosis factor blockers, Expert Opinion on Biological Therapy, 14:2, 151-156, DOI: 10.1517/14712598.2014.860441 To link to this article: http://dx.doi.org/10.1517/14712598.2014.860441
Published online: 05 Dec 2013.
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Date: 13 September 2015, At: 07:29
Downloaded by [Stockholm University Library] at 07:29 13 September 2015
Original Research
1.
Introduction
2.
Patients and methods
3.
Results
4.
Discussion
5.
Conclusion
Usefulness of QuantiFERON-TB Gold test in psoriatic patients under treatment with tumour necrosis factor blockers Rosita Saraceno†, Francesca Specchio, Andrea Chiricozzi, Loredana Sarmati, Massimo Amicosante, Maria Sole Chimenti & Sergio Chimenti †
University of Rome Tor Vergata, Division of Dermatology, Department of Internal Medicine, Rome, Italy
Objective: Infliximab is a human/mouse chimeric anti-tumour necrosis factor (TNF)-a antibody that is effective in the management of psoriasis. Anti-TNF treatments may reactivate latent tuberculosis infection (LTBI); therefore, screening for LTBI is mandatory before starting any anti-TNF-a therapy. The aim of this study is to evaluate the usefulness of the QuantiFERON-TB Gold (QFT-G) test in psoriatic patients under treatment with infliximab. Research design and methods: A retrospective study had been performed on patients affected by psoriasis who had been treated with infliximab from 2003 to 2012 at a single centre. Main outcomes measures: QFT-G was tested by a standard TB enzyme-linked immunosorbent assay, based on detection of interferon-g release from sensitized leucocytes exposed to the synthetic Mycobacterium tuberculosis antigens at baseline and every 6 months until the end of treatment. Results: A total of 140 patients were included. At baseline, 7 QFT-G tests were positive and 133 tests were negative. Of the 133 patients, 11 (8%) who were negative at baseline became QFT-G test positive during treatment. Of those 11 patients, 5 had a reversion during treatment. Of the 133 patients, 122 (92%) who were negative at baseline remained negative. Conclusions: It was found that the development of positive QFT-G tests, observed in 8% treated with infliximab, was not associated with pulmonary or extra-pulmonary tuberculosis. Keywords: anti-tumour necrosis factor-a blockers, infliximab, psoriasis, QuantiFERON-TB Gold tests, tumour necrosis factor-a Expert Opin. Biol. Ther. (2014) 14(2):151-156
1.
Introduction
Psoriasis is a chronic, inflammatory and debilitating disease of the skin, nails and joints, with an acknowledged and complex pathogenesis [1]. Treatments of moderateto-severe psoriasis include methotrexate, cyclosporine, fumarates, acitretin and biologics [2]. The latter comprises anti-tumour necrosis factor (TNF)-a agents largely used in the treatment of Crohn’s disease, rheumatoid arthritis (RA) and seronegative spondyloarthropathies. The TNF-a inhibitors such as infliximab, etanercept and adalimumab have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of psoriasis [3]. Infliximab, a human/ mouse chimeric anti-TNF-a antibody, is a highly effective treatment for both plaque-type psoriasis and psoriatic arthritis [4,5]. Treatment with all the anti-TNF-a agents increases the risk of latent tuberculosis infection (LTBI) reactivation [6], and there are few post-marketing reports on 10.1517/14712598.2014.860441 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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the development of both active tuberculosis (TB) and LTBI after initiation of anti-TNF-a therapy in psoriatic patients [7-10]. Recent Centers for Disease Control and Prevention recommendations suggest that tuberculin skin test (TST) and Interferon (IFN)-gamma release assay tests (IGRAs) (QuantiFERON-TB Gold [QFT-G], QuantiFERON-TB Gold In-Tube test and T-Spot) should be used as aids in diagnosing of M. tuberculosis infection [11]. Owing to possible false interpretation of the TST, especially in cases of immunosuppression, in Bacillus Calmette--Gue´rin (BCG)-vaccinated patients and in patients who have already started anti-TNF therapy, IGRAs may have an advantage over TST in terms of both sensitivity and specificity [12,13]. Information about the use of IGRAs in immunocompromised hosts has been provided by a growing number of reports; however, some limitations about the reproducibility of the test have been described [12-16]. Moreover, recently, the use of anti-TNF-a has been associated with the induction of positive QFT-G test in absence of a clinical correlations [12-17]. The aim of this study was to determine the performance of QFT-G test conversions and reversions in psoriatic patients under treatment with infliximab.
2.
Patients and methods
A retrospective review of the clinic database at the Department of Dermatology of the University of Rome Tor Vergata using the term ‘infliximab’ was undertaken. Using this database-generated list, all charts were reviewed, identifying case subjects seen in the day care unit and in the psoriasis clinic from 2003 (at the initiation of the database) to 2011. The baseline characteristics of age, sex, psoriasis phenotype, onset of the disease, comorbidities, previous systemic treatments for psoriasis and any concurrent medications were obtained. Exclusion criteria were subjects who were never treated with infliximab, the treatment period with infliximab was < 12 months, or the baseline QFT-G test was unavailable before commencing infliximab, or concurrent immunosuppressive drugs were prescribed. All patients treated with infliximab were unresponsive or contraindicated to at least two systemic conventional therapies. Patients with infectious disease, active or latent neoplastic disease (in the past 5 years), severe heart failure or demyelinating disorders were also excluded. All patients received infliximab as a continuous treatment and it was administered intravenously at weeks 0, 2, 6 and then every 8 weeks. The BCG vaccination status was reported either in patient medical history or assumed by the presence of vaccination scars. Clinical data were recorded and a questionnaire was administered to evaluate the risk of TB exposure [18]. 152
To rule out LTBI, IFN-g production was determined using QFT-G. The test was performed before starting the biological treatment (baseline) and every 6 months to monitor possible seroconversion. Peripheral blood was collected into three different tubes: the first containing no antigen (negative control or nil), the second containing TB-specific antigens and the third containing phytohaemagglutinin (mitogen or positive control). Blood samples were processed according to the manufacturer’s protocol (Cellestis: QuantiFERON-TB Gold package insert http://www.cellestis.com/IRM/Company/ ShowPage.aspx?CPID=1255). Results were evaluated according to the criteria established by the manufacturer, considering a result as positive if the IFN-g response of TB antigen minus nil was ‡ 0.35 IU/ml. Conversion was defined as a baseline IFN-g concentration < 0.35 IU/ml and a follow-up IFN-g concentration ‡ 0.35 IU/ml. Reversion was defined vice versa. All IFN-g release assays were retested at the same centre as the baseline IGRA. Analyses were carried out by the accredited Clinical Chemical Laboratories of the ‘Tor Vergata’ Polyclinic of Rome, Italy. Mantoux test was performed in positive QFT-G patients. Active TB was ruled out by chest X-ray and/or computed tomography (HRCT) in all participants with positive baseline QFT-G results and in those with conversions. TST was performed according to Mantoux method by injecting 5 UI of the antigen subcutaneously. An induration > 5 mm appearing after 48 h was considered positive. We used the cut off of 5 mm to define a positive tuberculin reaction because we considered our population as a population of immunosuppressed people as they were treated with immunosuppressive drugs [19]. Since, to date, there are not shared guidelines on the prophylaxis and timing of initiation of anti-TNF-a treatment, in our population, patients who showed positivity to QFT-G and/or TST underwent chemoprophylaxis with isoniazid 300 mg/day for 9 months [20-22]. Data for each of the study outcome variables were checked for normality of distribution using the Kolmogorov--Smirnov test. Quantitative variables were expressed as mean ± SD. Categorical variables were presented as numbers (%). The concordance level between QFT and TST assays was assessed with chi-squared tests and the strength of agreement was examined using Cohen’s kappa. Kappa values > 0.75 represented excellent agreement, values between 0.40 and 0.75 represented fair to good agreement and values < 0.40 represented poor agreement beyond chance.
3.
Results
A total of 169 patients treated with infliximab during the study period were analyzed (Table 1). Of the 140 patients that met the study criteria for inclusion, 93 were male and 47 were female. The mean age was 52 years (± 14), with a range of 23 to 84 years. Of the 140 subjects, 72 (52%) and 68 (48%)
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Table 1. Demographical data and clinical features of the study population.
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Number of patients Mean age (years ± SD) Male/female (n) Onset of the disease (years ± SD) Plaque-type psoriasis (n, %) Psoriatic arthritis (n, %) Previous immunosuppressive systemic therapies Mean number of previous immunosuppressive systemic therapies Mean number of previous biological agents TB risk Chest X-ray at baseline and during treatment
140 52 (±14) 93/47 28 (±15) 72 (52%) 68 (48%) 137/140 (97%) 2.5 0.4 31/140 (22%) 140/140 (100%)
Table 2. Agreement rates between TST and QFT-Gold assays at baseline in the study population.
TST
TB GOLD +
-
+
4
6
-
3
127
Patients agreement between the two tests was moderate according to Cohen’s kappa score (k = 0.4).
subjects had plaque-type psoriasis and psoriatic arthritis, respectively. The mean period of treatment was 3 years. The main risk factor for TB in the study population was the condition of immunosuppression secondary to prolonged immunosuppressive treatments. Only three patients were never treated with conventional immunosuppressive therapies because of concomitant comorbidities. None of the 140 subjects were HIV-positive, malnourished or were previously exposed to patients with active TB. Additional risk factors for TB infection were recorded in 31 of 140 patients: smoking more than 20 cigarettes a day (n = 11); diabetes mellitus (n = 13); travelling to countries that have high rates of TB (n = 4) and professional exposure (n = 5). Of the 169 patients, 29 were excluded from the study for the following reasons: i) had positive baseline QFT-G (n = 7); ii) were treated in association with methotrexate (n = 2); iii) did not have baseline or routine QFT-G available (n = 9); iv) were lost to follow up (two patients continued treatment in a different centre); and v) the duration of infliximab treatment was < 12 months (n = 9). In the latter group, five patients discontinued the therapy due to lack of efficacy and four patients discontinued for adverse events. Reasons for discontinuation were allergic reaction (urticaria and oedema) during the infusion (n = 1), pulmonary infection (n = 2) or pregnancy (n = 1). At baseline, 7 patients were QFT-G positive and 133 patients were negative. Four QFT-G positive patients
were also TST positive (Table 2). Patients agreement between the two tests was moderate according to Cohen’s kappa score (k = 0.4). The 7 patients who were QFT-G positive prior to starting infliximab underwent chest-X ray and/or HRCT to exclude active TB. Patients who were considered affected by LTBI began TB prophylaxis, according with the current recommendations [20-22]. In these patients, anti-TNF-a treatment was postponed until after 6 months of TB prophylaxis. Of the 133 patients, 11 (8%) patients who were negative at baseline became QFT-G positive during the study period. Of the 11 patients, 10 were men and the mean age was 51 years. None of the 11 patients had previously received the BCG vaccine. Of the 11 patients who became QFT-G positive, all had negative Mantoux tests except two patients: of those, one had positive Mantoux test of 10 mm diameter and one was lost to follow up. Patients who became QFT-G positive during the treatment withdrew from the anti-TNF-a therapy and began TB prophylaxis as reported below. The mean time of conversion was 40 months (mean value of QFTG = 3.7 IU/ml ± 5.17). Of those 11 patients, 5 had subsequent reversion to QFTG negative (see Figure 1). The mean period of reversion was 16 months. None of the 11 study subjects who turned QFT-G positive developed active TB within the observational period of > 3 years. A total of 122 patients who were QFT-G negative at the beginning remained stably QFT-G negative for the whole duration of infliximab treatment. 4.
Discussion
In this study we evaluated the use of IGRA in the serial testing of psoriatic patients under long-term treatment with infliximab. We observed a strong overall concordance between baseline and follow up in subjects with negative QFT-G. In contrast, in patients presenting a conversion during treatment, reversions occurred in 50% of the study subjects. In our study, 11 psoriatic patients developed QFT-G positivity during treatment with infliximab. Interestingly, 10 of the 11 patients who developed QFT-G conversion during infliximab treatment were men, thus suggesting a gender correlation. Moreover, we found that in the long-term treatment (> 3 years of follow up), the development of QFT-G positivity was not associated with a risk of TB reactivation. Similar to our findings, Garcovich et al. [23] have previously assessed, in a prospective study, the role of QFT in the diagnosis of LTBI during systemic anti-TNF-a treatment in psoriasis patients. They showed that single-test QFT-based screening strategy for LTBI was proven effective in reducing the incidence of false-positive LTBI cases and, thereby, in preventing unnecessary TB chemoprophylaxis. During 12 months of continuous anti-TNF-a treatment, the authors found that QFT conversions occurred in 10% (five cases) of the initial study population (n = 50) with three QFT/TST
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Figure 1. The graph shows longitudinal variations in IFN-g in 11 psoriatic patients treated with infliximab; five of those had subsequent reversion to QFT-G negative. The IFN-g response to M. tuberculosis-specific antigens was measured by QFT-G before and during treatment. The cut-off value for a positive result was 0.35 IU/ml. The reasons for treatment discontinuation were not related to the QFT-G results.
concordant cases after 6 months and two more QFT/TST discordant cases after 12 months of treatment. Isoniazid therapy was initiated for a 6-month-long course along with previous anti-TNF-a treatment. The authors suggested that a single-test QFT-based screening strategy for LTBI in psoriasis patients receiving continuous long-term anti-TNF-a treatment could reduce the incidence of false-positive LTBI cases, preventing unnecessary TB chemoprophylaxis. In contrast to the abovementioned research, our population was larger and was studied for a longer period. Moreover, we included only patients who were treated with infliximab, whereas Garcovich et al. included three patients who were treated with infliximab and the rest were treated with etanercept and adalimumab. The use and the reliability of TST as a tool for serial testing are limited by cross-reactivity due to i) BCG vaccination and ii) exposure to non-tuberculous mycobacteria, nonspecific variations and false positivity mimicked by koebnerization in the site of the antigen inoculation in psoriatic patients [12]. Moreover, TST shows low specificity in vaccinated subjects and lower sensitivity in immunosuppressed patients, compared to healthy subjects. For all these argumentations, in the latest years, QFT-G test has been preferred since the diagnostic accuracy in detecting LTBI is higher [16]. QFT-G test is an in vitro blood test measuring the production of IFN-g by T cells exposed to antigens highly specific for Mycobacterium tuberculosis. It seems to be unaffected by prior BCG vaccination and, thus, offers an increased specificity compared to TST [17]. QFT-G test detects levels of IFN-g, which it might be theoretically produced by both activated T cells, likely because of a concomitant TB infection, and 154
memory T cells, as pre-sensitized to TB antigens in vaccinated or previously exposed subjects. The development of QFT-G positivity during anti-TNF-a therapy is a well-known occurrence that has been reported in RA, spondyloarthritis, intestinal bowel disease and psoriasis [20]. Infliximab is highly effective in treating these conditions. It is an IgG1 murine-human anti-TNF-a antibody binding both soluble and transmembrane TNF-a [24]. Modulating the immune response, it may be associated with an increased risk of reactivation with infectious granulomatous pathogens, such as M. tuberculosis. Although not excessive, the risk of reactivation requires screening tests [6]. It is hard to explain how IGRA-negative subjects at the baseline might develop positivity to IGRA test while undergoing treatment with infliximab. It could be postulated that positivity to IGRA is considered a risk of reactivation of TB infection or it may be a sign of a de novo (new) infection contracted during therapy. However, longitudinal studies have revealed a considerable fluctuation in IFN-g responses to serial testing in TB patients or in TB-exposed healthcare workers [25-28]. These fluctuations might be attributed to limitations in the accuracy of IGRAs or to actual fluctuations in IFN-g levels in the same patient. Some increases in IFN-g levels might be attributed to new infection or to a boost following TST. Some decreases in IFN-g levels might be attributed to anti-mycobacterial treatment. However, for the most part, fluctuations in IFN-g levels among serially tested patients reported in longitudinal studies remain unexplained and nonspecific. The magnitude of these fluctuations can be of sufficient size to misinterpret the test in terms of conversion
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Usefulness of QFT-G test in psoriatic patients under treatment with TNF blockers
or reversion, especially when the IFN-g levels are near cut points dissecting positive and negative results. The correct meaning and evaluation of this laboratory data, therefore, remain unclear. In particular, this phenomenon in patients treated with anti-TNF-a drugs could be related to a possible interference between the anti-TNF-a activity and the immune response to TB infection. Three possible mechanisms could be hypothesized: i) it has been shown that infliximab interferes in regulatory T-cell (Treg) activity, reducing IL-10 synthesis [29]; it is likely that IFN-g production is modulated by Treg and thus, even a slight production might be detectable and test results as positive; ii) infliximab modulates the activity of T cells that bear transmembrane TNF-a, but quiescent memory T cells, previously sensitized to TB antigens, might be not affected by infliximab because antiTNF-a agents are immunomodulators and not immunosuppressants because immune pathways still remain operative (the reason why serious infections are not so common); iii) it is known that QFT-G is not affected by previous vaccination, but it is reasonable that memory T cells, whether they have been previously exposed to M. tuberculosis antigens, might become reactive performing the in vitro stimulation with TB gold quantiferon antigens. It has been demonstrated that infliximab induces apoptosis in activated, but not quiescent, T cells [30]. Is it likely that the fluctuation of QFT-G in patients treated with anti-TNF-a might represent just an activation of clonal T cells without a pathological meaning? And, if it is so, are we overtreating patients with useless and possibly toxic antitubercular prophylaxis? All these arguments lead us to carefully consider the Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Conclusion
Infliximab may reactivate LTBI and for this reason screening for LTBI is mandatory before starting therapy and during treatment. In our study, we observed 8% of development of positive QFT-G tests, and reversions occurred in about 50% of psoriatic patients during infliximab administration. However, since positivity was not associated with pulmonary or extrapulmonary TB, the QFT-G fluctuations might be attributed to limitations in the accuracy of IGRAs or to actual fluctuations in IFN-g levels in the same patient possibly induced by the anti-TNF-a interference to the immune response to TB test. Finally, even though the small study population and the IGRA test used represent a limitation of this study, the results allow us to hypothesize a low risk of progression to active TB in patients developing QFT-G conversion without any recent, certain and prolonged exposure. Therefore, before beginning TB prophylaxis in patients with QFT-G test conversion, the possibility of a false-positive IGRA result should be rule out by TST and radiological examinations.
Declaration of interest The authors have received speaker fees from MSD, the manufacturer of infliximab.
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Affiliation
Rosita Saraceno†1 MD, Francesca Specchio1 MD, Andrea Chiricozzi1,5 MD, Loredana Sarmati2 MD, Massimo Amicosante4 MD, Maria Sole Chimenti3 MD & Sergio Chimenti1 MD † Author for correspondence 1 University of Rome Tor Vergata, Division of Dermatology, Department of Internal Medicine, Rome, Italy Tel: +390620902743; Fax: +390620902742; E-mail: [email protected] 2 University of Rome Tor Vergata, Division of Infectious Diseases, Department of Internal Medicine, Rome, Italy 3 University of Rome Tor Vergata, Division of Rheumatology, Department of Internal Medicine, Rome, Italy 4 University of Rome Tor Vergata, Department of Biomedicine and Prevention, Rome, Italy 5 The Rockefeller University, Laboratory for Investigative Dermatology, New York, NY, USA
