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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To investigate QuantiFERON-tuberculosis Gold (QFT-G) assay and tuberculin skin test (TST) for latent tuberculosis (TB) infection (LTBI) in patients with rheumatoid arthritis (RA) treated with adalimumab.

Methods

We prospectively followed up 43 RA patients who received adalimumab therapy and underwent serial TSTs and QFT-G assays. TST was performed using Mantoux method and QFT-G assay was examined by measuring interferon-γ levels in whole blood samples that were incubated with early secretary antigenic target-6 and culture filtrate protein 10.

Results

Before starting adalimumab therapy, 8 RA patients (18.6%) had positive and 35 (81.4%) had negative TST results. All 8 RA patients with positive TST results were diagnosed as LTBI and received isoniazid prophylaxis (INHP) 1 month before starting adalimumab therapy. None of these 8 RA patients developed active TB 2 years after completing INHP. A high rate (10 [37.0%] patients) of TST conversion was observed among 27 patients who had completed 12-month adalimumab therapy. Of these 10 patients with TST conversion, 2 patients had positive QFT-G results and 1 developed active TB disease. Among 17 RA patients who did not have TST conversion after 12-month adalimumab therapy, 1 patient who had a positive QFT-G result developed active TB disease. Of all 43 RA patients who received adalimumab therapy, 4 (9.3%) developed active TB after starting adalimumab therapy.

Conclusion

The application of TST for detecting LTBI is limited in RA patients by the frequent presence of anergy. Combined QFT-G assay and TST can aid in detecting LTBI in RA patients receiving adalimumab therapy.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Despite the extensive implementation of BCG vaccination for newborn babies and for 7–10-year-old school children without a characteristic BCG scar in Taiwan, tuberculosis (TB) was prevalent in a notification rate of 74.6 per 100,000 populations in 2002 (1). The increased prevalence of active TB, which has been reported in patients with rheumatoid arthritis (RA), is thought to be associated with disease-related disturbances in immune function as well as treatment with immunosuppressive agents (2, 3). Recently, treatment with tumor necrosis factor α (TNFα) antagonists has been found to be associated with an increased TB risk (4–6). As noted, active TB in patients with RA receiving TNFα antagonists mainly appears to be due to reactivation of latent TB infection (LTBI) (7). Adalimumab is the first fully human anti-TNF monoclonal antibody for RA treatment (8). Prior to implementing routine TB screening in adalimumab RA clinical trials, the rate of developing TB disease increased (9). Guidelines have recommended that screening for TB exposure should be carried out before the initiation of TNFα antagonists and appropriate prophylaxis should be initiated before starting anti-TNF treatment if evidence of LTBI exists (10, 11). Recent studies demonstrated that isoniazid prophylaxis (INHP) could effectively prevent the reactivation of TB (12, 13).

Tuberculin skin test (TST) with an intradermal injection of purified protein derivative (PPD) from Mycobacterium tuberculosis culture filtrate has been widely used as a diagnostic tool for LTBI (14). However, the TST has some drawbacks, including variability in test application and reading, and low specificity as PPD presenting in nontuberculous mycobacteria (NTM) and in BCG strains (15, 16). The TST-positive rate (induration diameter ≥10 mm) was 47% in a group of patients ages 20–59 years and up to 64% in a group with household contact of TB in Taiwan. In addition, the annual incidence of disease caused by NTM was 21.5 per 100,000 patients in 2002 (17, 18). A recent diagnostic method, QuantiFERON-TB gold (QFT-G; Cellestis Limited, Carnegie, Victoria, Australia) is an in vitro test for M tuberculosis infection that measures interferon-γ (IFNγ) secreted by T cells stimulated with mixtures of synthetic peptides including the early secretary antigenic target-6 (ESAT-6) and culture filtrate protein 10 (CFP-10) that are specific to M tuberculosis (16, 19–21). The recent Centers for Disease Control and Prevention (CDC) guidelines suggest that QFT-G can replace TST under all circumstances in which the TST is currently used, including periodic testing (19, 22). Recent studies demonstrated that the IFNγ-based assay appeared promising for TB screening in patients with RA prior to anti-TNFα therapy (13, 23) and for serial testing of TB in health care workers (24). There are limited data on QFT-G performance in patients with RA as an immune-compromised population. To our knowledge, there are no reports on serial testing of TSTs and QFT-G assays in patients with RA receiving anti-TNFα therapy.

The aim of the present study was to investigate the performance of QFT-G assays combined with TSTs in periodic testing for TB in patients with RA treated with adalimumab in Taiwan. The results of TSTs and QFT-G assays and QFT-G conversions or reversions were evaluated. We also evaluated the diagnostic accuracy of QFT-G and TST in patients with RA who developed active TB disease after anti-TNFα therapy.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Patients.

Forty-three patients with active RA (35 women and 8 men, mean ± SD age 52.6 ± 10.2 years) fulfilling the American College of Rheumatology (formerly the American Rheumatism Association) 1987 revised criteria for RA (25) were enrolled. All RA patients, who continued the open-label extension portion of the adalimumab trial designed to demonstrate the long-term safety of adalimumab, received both QFT-G assays and TSTs. Active arthritis was defined as having a Disease Activity Score in 28 joints (DAS28) (26) of at least 5.0. All patients received oral corticosteroids (prednisolone 5–10 mg daily), nonsteroidal antiinflammatory drugs, and oral methotrexate (12.5–17.5 mg weekly), but no other disease-modifying antirheumatic drugs, for at least 1 month prior to study enrollment. All patients had previously been given a BCG vaccination at birth, and 3 patients received a second dose in the first grade of elementary school due to no visible BCG scar. Patients were excluded from the study if they had clinically active TB or radiographic evidence of a fibrocalcified lesion in the upper lung field. The Clinical Research Ethics Committee at Taichung Veterans General Hospital approved the study protocol, and informed consent was obtained from each participant.

TST for LTBI in RA patients treated with adalimumab.

Before starting adalimumab therapy, TB screening consisting of a detailed medical history, chest radiographs, and TSTs were performed in all RA patients. The TST was performed with an intradermal injection of 2 tuberculin units (TU) of PPD RT-23 (Staten Serum Institute, Copenhagen, Denmark) into the ventral surface of the forearm in each patient according to the Mantoux method. The size of induration was measured 48–72 hours later. The dose of tuberculin administered is bioequivalent to the international standard of 5 TU PPD-Siebert (PPD-S) (27). The interpretation depends on examinations by palpation and ball-pen methods. If the induration diameter is ≥5 mm, the result is defined as a positive TST (28). The 2-step TST was not performed in any of our patients at baseline screening. We performed serial TSTs at the 12th and 24th months of adalimumab therapy in all RA patients who had negative TST results at baseline. TST conversions were defined as an induration diameter ≥5 mm with an increment of 10 mm more than baseline (24).

QFT-G assay for LTBI in RA patients treated with adalimumab.

A total of 35 RA patients who had received adalimumab therapy for 1 year were enrolled for the QFT-G assay. The QFT-G test was performed according to the manufacturer's instructions (Cellestis). Briefly, 4 aliquots of heparinized whole blood was incubated with ESAT-6, CFP-10, mitogen (phytohemagglutinin [PHA] as a positive control), and nil antigens (as a negative control). After 12–18 hours (overnight) of incubation at 37°C in a humidified atmosphere, plasma was aspirated from each well and the amount of IFNγ was measured by enzyme-linked immunosorbent assay. As recommended by the manufacturer and a previous study (29), the results of QFT-G were considered positive if the IFNγ level in the antigen-stimulated wells (ESAT-6 or CFP-10) was ≥0.35 IU/ml after subtracting the level of the nil well, and negative if the IFNγ level in the antigen-stimulated wells was <0.35 IU/ml (after subtracting the level of the nil well) and if the IFNγ level of the mitogen well (after subtracting the level of the nil well) was ≥0.5 IU/ml. The result of QFT-G was considered indeterminate if the IFNγ level in the antigen-stimulated wells was <0.35 IU/ml and in the mitogen well was <0.5 IU/ml. We performed serial QFT-G assays in each RA patient at the 12th and 24th month of adalimumab therapy. QFT-G conversions were defined as baseline IFNγ <0.35 IU/ml and followup IFNγ ≥0.35 IU/ml. QFT-G reversions were defined as baseline IFNγ ≥0.35 and followup IFNγ <0.35 IU/ml (24).

Statistical analysis.

We assessed the concordance level between TST and QFT-G assay using the chi-square tests. The strength of this agreement was examined using Cohen's kappa, with kappa values >0.75 representing excellent agreement beyond chance, values 0.40–0.75 representing fair to good agreement beyond chance, and values <0.40 representing poor agreement beyond chance. P values less than 0.05 were considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Clinical characteristics of RA patients.

All RA patients had active disease (median DAS28 score 6.54, range 5.63–7.37). The radiographic stage (30) was II (46.5%) and III (53.5%) for RA patients. Before starting adalimumab therapy, 8 RA patients (18.6%) had positive TST results and 35 (81.4%) had negative TST results. There was no significant difference in demographic data, disease duration, DAS28 score, serum C-reactive protein levels, radiographic staging, proportion of extraarticular features including Sjögren's syndrome and interstitial lung disease, positive rate of serum rheumatoid factor, dose of corticosteroids, or dose of methotrexate between RA patients with positive TST results and those with negative TST results before starting adalimumab therapy (Table 1). All 8 RA patients with positive TST results were diagnosed as having LTBI and received INHP 1 month prior to the first dose of adalimumab. None of these 8 RA patients developed active TB disease more than 2 years after the completion of INHP.

Table 1. Demographic data, clinical characteristics, and laboratory findings of rheumatoid arthritis patients with positive and negative TST results before adalimumab therapy*
CharacteristicsPositive TST (n = 8)Negative TST (n = 35)P
  • *

    Values are the mean ± SD unless otherwise indicated. TST = tuberculin skin test; NS = nonsignificant; DAS28 = Disease Activity Score in 28 joints; CRP = C-reactive protein; RF = rheumatoid factor.

Age at onset, years42.5 ± 8.145.4 ± 11.4NS
Female sex, %87.577.1NS
Disease duration, years8.4 ± 4.77.7 ± 4.1NS
DAS28 score6.7 ± 0.46.5 ± 0.4NS
CRP level, mg/dl1.82 ± 0.851.48 ± 0.66NS
Radiographic staging, %   
 Stage II25.051.4NS
 Stage III75.048.6NS
Extraarticular features, %12.511.4NS
RF positive, %75.085.7NS
Daily corticosteroid dose, mg9.1 ± 1.48.3 ± 1.7NS
Weekly methotrexate dose, mg14.7 ± 1.614.9 ± 1.3NS

Characteristics of active TB disease in RA patients receiving adalimumab therapy.

Of the 43 RA patients who received adalimumab therapy, 4 (9.3%) developed active TB disease, proved by positive culture or tissue biopsy, in a median interval of 14 months (range 10–18 months) after starting adalimumab. All 4 patients (2 men and 2 women) were receiving oral corticosteroids at a daily dosage of 7.5–10 mg and methotrexate therapy at a weekly dosage of 15 mg at the time of TB diagnosis. All of our RA patients who developed active TB disease had extrapulmonary involvement, including cervical lymph nodes (2 of 4), pleura (2 of 4), and proximal interphalangeal joint (1 of 4). These patients were treated successfully with standard anti-TB treatment without adverse effects. No significant difference was observed in demographic data, radiographic staging, cumulative doses of corticosteroids, or disease activity between RA patients with active TB disease and those without active TB disease (data not shown).

Combining the results of QFT-G assays and TST for RA patients receiving adalimumab therapy.

During the first year of adalimumab therapy, 8 RA patients who discontinued the treatment due to either active TB disease (n = 2) or other adverse effects (n = 6) were not assessed by QFT-G assay due to early withdrawal. All of these patients had negative TST results at baseline screening. A total of 35 RA patients received a series of QFT-G assays and TSTs. The TST and QFT-G results are shown in Figure 1. Of 27 RA patients who had negative TST results initially and completed 12 months of adalimumab therapy, TST conversion was observed in 10 (37.0%). Among these patients with TST conversion, positive QFT-G results were found in only 2 patients, of whom 1 developed active TB disease. The other patient who did not develop active TB had a weak IFNγ response (ESAT-6 0.57 IU/ml). Seven patients had negative QFT-G results and 1 patient had an indeterminate result, with none developing active TB disease during a 2-year followup period. Among 17 RA patients who had no TST conversion after 12 months of adalimumab therapy, 1 patient with a positive QFT-G result developed active TB disease. Fifteen patients had negative QFT-G results and 1 patient had an indeterminate result, with none developing active TB disease during a 2-year followup period.

thumbnail image

Figure 1. Flow chart showing the distribution of QuantiFERON (QFT) Gold (Cellestis Limited) results of rheumatoid arthritis (RA) patients with positive and negative tuberculin skin test (TST) results who received adalimumab therapy. INHP = isoniazid prophylaxis; TB = active tuberculosis disease; QFT (+) = positive QFT result; QFT (I) = indeterminate QFT result; QFT (−) = negative QFT result; weak QFT = weak interferon-γ response in QFT assay; ∗ = age/sex in parentheses.

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After the completion of 24 months of adalimumab therapy, a third TST for 16 RA patients who had negative TST results and did not contract active TB disease and a second QFT-G assay for all 35 RA patients were performed. We found no TST conversion in any of the 16 RA patients who had negative TST results. Among these patients, the results of the second QFT-G assay showed that 1 patient who had completed anti-TB chemotherapy had a reversion, 1 patient had a previous indeterminate result turn positive, and the rest of the patients had no conversion or reversion. Of 10 RA patients who had TST conversion, the second QFT-G assay showed that reversion occurred in 2 patients, including 1 with a weak IFNγ response and another who had completed anti-TB chemotherapy; a negative result was observed in 1 patient whose previous result had been indeterminate.

Among 8 RA patients who had positive initial TST results and had completed 9 months of INHP as well as 12 months of adalimumab therapy, 3 patients had positive QFT-G results. Of these, 2 (66.7%) showed QFT-G reversion and 1 had a persistent positive QFT-G result, and none developed active TB disease during a 2-year followup period.

Agreement and kappa statistic between TST and QFT-G assay.

Using 5-mm induration diameter as the TST cutoff value, the agreement between TST and QFT-G was 60.0% (95% confidence interval [95% CI] 43.8%, 76.2%) with a kappa value of 0.215 (95% CI −0.022, 0.452). Using 10-mm induration diameter as the TST cutoff value, the agreement between TST and QFT-G was 68.6% (95% CI 60.2%, 77.0%) with a kappa value of 0.306 (95% CI 0.032, 0.580). Using 15-mm induration diameter as the TST cutoff value, the agreement between TST and QFT-G was 71.4% (95% CI 63.4%, 79.4%) with a kappa value of 0.342 (95% CI 0.054, 0.630).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

RA patients often have compromised immune function as a result of underlying diseases, increased age, comorbidities, and the use of immunosuppressive agents (2, 3, 31); an increased risk of active TB disease has been reported in those treated with TNFα antagonists (4–6). In the present study, 4 (9.3%) of 43 RA patients developed active TB disease during 2-year adalimumab therapy. Similar to previous reports showing a high prevalence of extrapulmonary TB in RA patients receiving anti-TNF therapy (5, 6), all of our RA patients who developed active TB disease had extrapulmonary involvement. The high proportion (100%) of extrapulmonary involvement found in this study suggested that reactivation of LTBI may be one cause of active TB disease in RA patients receiving adalimumab therapy (32). Considering the longer interval (a range of 10–18 months) between starting adalimumab therapy and the onset of active TB disease, however, a recent exposure to TB infection is also a probable cause of TB in our patients, who were immunocompromised and lived in Taiwan, which has a high prevalence of TB. Additionally, all 8 patients who had positive TST results at baseline screening and completed INHP did not develop active TB disease. Our results were consistent with previous reports indicating the efficacy of INHP in preventing reactivation of LTBI (12, 13, 33).

Our data showing 81.4% negative TST results at baseline screening in patients with active RA were in accordance with the results reported by Ponce de Leon et al (70.6%) (34). Use of immunosuppressive agents and immune dysfunction related to RA may be the causes for the reported negative TST results in our study as well as other previous reports (34, 35). Additionally, a recent study demonstrated a significant reduction in the reactivity against M tuberculosis in RA patients during adalimumab therapy (36). Our results support previous reports claiming that the clinical utility of TST is limited in detecting LTBI in patients receiving immunosuppressive therapy (34, 35).

An interesting finding of our study was the high rate (37.0%) of TST conversion observed among 27 patients who completed 12 months of therapy with adalimumab. The TST conversion might have been caused by NTM cross-reaction, delayed booster effect, and true recent TB infection. Although NTM infection might have caused the TST conversion, the influence was less than that of TB because the annual incidence (per 100,000 patients) of diseases caused by NTM was lower than TB in Taiwan (18), and the absolute impact of NTM on TST was very low (0.1–2.3%), even in populations with a high prevalence of NTM (37). In a recent report by Hatemi et al, the booster phenomenon was observed in 29% of patients with RA (38). Because the 2-step TST was not performed on any patient at baseline screening in the present study, the delayed booster response of repeated TST might be the probable cause of TST conversion in a predominantly BCG-vaccinated population (39–42), especially in patients who were given BCG after infancy (37). Moreover, recent studies have also demonstrated that TNFα inhibitors do not suppress the tuberculin skin testing, or affect the skin conversion rate (38, 43). Besides the NTM cross-reactivity or delayed booster effect, we think the other skin conversions might be due to true recent TB infection. Additionally, application technique and interreader variability in TST may have biased the results of this study. At the time of our investigation, no available guidelines recommended periodic TSTs for RA patients receiving TNFα inhibitors. Furthermore, therapeutic strategies of prophylactic therapy for patients with TST conversions are only recommended for children younger than 12 years, not for adults, by Taiwan's CDC. Although INHP was not administered to our patients with TST conversions, we closely monitored these patients and thoroughly assessed them to detect active TB disease early. We also learned from this study that standard 2-step TSTs should be performed in RA patients at baseline screening before starting TNFα inhibitors. This is to avoid mislabeling the true TST conversion as a booster phenomenon during periodic PPD testing. In addition, periodic TSTs should be considered in the followup for RA patients receiving adalimumab therapy, and any patient with TST conversion should receive prophylactic therapy for TB in accordance with current guidelines (44).

Of our 10 patients with TST conversion, only 2 patients had positive QFT-G results: one developed active TB disease and the other who did not develop active TB had a weak IFNγ response. None of the other 8 patients with TST conversion developed active TB disease. In agreement with previous studies reporting an increased risk of TB disease within 2 years of ESAT-responsive contacts (45) and those showing that in vitro blood assays with TB-specific antigens had better specificity than TSTs (23, 46, 47), our data supported the usefulness of QFT-G assays in detecting TB infection in BCG-vaccinated patients receiving adalimumab therapy. A higher specificity of QFT-G assay would help patients avoid unnecessary INHP and its associated toxic effects (48).

Using 5-mm induration diameter as the TST cutoff value in this study, the overall agreement between the TSTs and QFT-G assays was 60.0%, with a kappa coefficient of 0.215, indicating poor agreement. Our results were consistent with previous studies reporting an overall agreement of 70.2–97.6% between these tests, with kappa values of 0.25–0.79 (15, 49, 50), and with 1 study demonstrating even less agreement among BCG-vaccinated patients compared with nonvaccinated individuals (51). We speculate that the poor agreement could be ascribed to several factors, including the distinct immunologic mechanisms responsible for positive results of TSTs or QFT-G assays, the different antigens used in the 2 tests, and the presence of booster effects in TST.

Similar to the results of recent studies (13, 23, 52), 2 of our RA patients (5.7%) who received immunosuppressive agents, including adalimumab therapy, had an indeterminate QFT-G result. The inclusion of positive PHA control was allowed for the identification of RA patients who had an indeterminate QFT-G result due to their inability to evoke an in vitro immune response, which may indicate the effect of immunosuppressive agents (52, 53).

In this study, QFT-G reversion was observed in 2 RA patients who had completed INHP and in another 2 patients after the completion of anti-TB chemotherapy against their TB disease. This finding was supported by a progressive decrease in the frequency of M tuberculosis antigen-specific IFNγ-secreting T cells and the reversion to negative in the IFNγ release assay during anti-TB chemotherapy (54, 55). Our data indicate that QFT-G assays might aid in monitoring the efficacy of anti-TB therapy, with QFT-G reversion as a marker of successful treatment. However, the number of enrolled patients was small and therefore these data have to be confirmed in a larger study.

In conclusion, patients with RA receiving immunosuppressive therapy, which may lead to false-negative TST results, should undergo serial tests for LTBI and receive INHP in accordance with current guidelines. As suggested by Pratt et al (13), reliable results of QFT-G assays can prospectively help clinicians to accurately identify the group with high risk of developing TB disease and provide these patients with INHP prior to anti-TNF therapy. Although the sample size of this study was too small for us to come to definite conclusions, we still highly recommend that QFT-G assay be added as a part of the screening procedure for the detection of LTBI in patients with RA prior to the initiation of TNFα antagonist therapy.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Dr. Lan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Chen, Lan.

Acquisition of data. Chen, Shen, Tsu-Yi Hsieh, Chia-Wei Hsieh.

Analysis and interpretation of data. Chen, Shen, Tsu-Yi Hsieh, Lan.

Manuscript preparation. Chen, Tsu-Yi Hsieh.

Statistical analysis. Chen, Lan.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
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