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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

Objective

Reactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti–tumor necrosis factor (anti-TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase III Program (3 with rheumatoid arthritis, 1 with psoriatic arthritis, and 1 with ankylosing spondylitis) through 1 year among 2,210 patients receiving golimumab.

Methods

Data from global studies were used for an in-depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti-TB therapy.

Results

No active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients not treated with isoniazid by week 52 (in 2 patients by week 24); all of the patients had negative TB screening tests (per the local guidelines) and resided in countries with high background rates of TB. No deaths were due to TB. Across all of the groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (<3 times the upper limit of normal).

Conclusion

Comprehensive TB screening kept the number of active TB cases relatively low despite conducting the studies in TB-endemic regions. Treatment for latent TB infection appeared effective, since no patients treated for latent TB had TB reactivation. Concurrent treatment with golimumab and anti-TB medication was generally well tolerated. Clinicians should remain vigilant for development of active TB after initiation of TNF inhibitors, since prompt diagnosis and treatment can improve outcomes.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

Reactivation of Mycobacterium tuberculosis infection is a major complication in patients with inflammatory diseases treated with anti–tumor necrosis factor (anti-TNF) agents. Vigilant screening and appropriate treatment for latent tuberculosis (TB) infection before initiation of TNF inhibitors, including prompt diagnosis of active TB cases, can decrease morbidity and mortality related to TB infection (1).

Historically, patients have been screened for the presence of active or latent TB using the tuberculin skin test (TST); however, its limitations include false-positive or false-negative reactions such as those occurring in patients who received the BCG vaccine or those who are immunocompromised (1). Moreover, the TST is known to have limitations related to variability in placement, quantitative assessment, and host anergy. Newer TB testing methods, including the QuantiFERON-TB Gold In-Tube (QFT-GIT) test (Cellestis) (2) and the enzyme-linked immunospot–based T-SPOT.TB assay (Oxford Immunotec) (3), have shown greater sensitivity and specificity in detecting latent TB infection.

Previously, we described the results of analyses comparing the performance of an interferon-γ–release assay (IGRA; i.e., QFT-GIT) versus a TST for latent TB infection screening prior to initiating anti-TNF therapy using an integrated analysis of pooled TB screening data from 5 studies in the Golimumab Phase III Program (4). This report describes all active TB cases that were reported by week 52 across the Golimumab Phase III Program, including the GO-BEFORE, GO-FORWARD, GO-AFTER, GO-REVEAL, and GO-RAISE studies (4). Pooled data through week 24 from these 5 studies were evaluated for potential hepatotoxicity in patients treated for latent TB versus those not receiving treatment.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

The patients were screened for TB using the TST and an IGRA (i.e., QFT-GIT). Eligible patients had no history of latent or active TB prior to screening (in GO-AFTER, patients with a history of latent TB with adequate treatment within 3 years were eligible) and no signs or symptoms of active TB. Patients who reported recent close contact with anyone with active TB were referred to a TB specialist and, if warranted, were treated for latent TB infection before receiving the study agent. Patients with either a positive TST or IGRA result, with active TB ruled out, were to receive appropriate treatment for latent TB prior to or simultaneously with the first dose of the study agent. Chest radiographs were to be performed within 3 months of receiving the first study injection and were read at local sites. The study participants were questioned about previous BCG vaccination.

The TST was performed according to the Mantoux method, using 5 tuberculin units (TU) of purified protein derivative (PPD) standard or 2 TU of PPD RT-23 from the Statens Serum Institut. Local country guidelines for an immunosuppressed host that were in place at the time of the studies were used to classify TST results as positive; however, an induration of at least 5 mm was considered to be positive if no local country guidelines existed. For the IGRA, a central laboratory performed the enzyme-linked immunosorbent assay–based testing and interpreted the results according to the manufacturer's criteria. Positive test results were confirmed by duplicate testing of the same sample. Initially indeterminate IGRA results were repeated on a new sample, and the final result determined patient eligibility. Patients with an indeterminate IGRA result and a negative TST could enter the trials without treatment for latent TB infection. Local country guidelines for immunocompromised persons were also used to determine the treatment regimen for latent TB infection, or if no guidelines existed, US guidelines had to be followed. Patients who discontinued anti-TB medications prematurely were required to be discontinued from the study.

Patients were evaluated for signs and symptoms of active TB every 4–12 weeks. If TB was suspected during the study, repeat TB testing (TST, IGRA, and chest radiograph) was recommended. The study agent was stopped in all patients who developed active TB. Routine laboratory analyses, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, were measured every 4–8 weeks at a central laboratory.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

Active TB case reports through week 52 by study.

Among 2,303 patients randomized in the 5 studies, 2,210 received golimumab, including 80% with at least 1 year of exposure (4). Three hundred seventeen patients received treatment for latent TB, with ∼90% initiating treatment within 1 month of the first study injection and the remainder initiating treatment >1 month prior to the first study injection. Of the 317 patients, 161 had a positive QFT-GIT, 215 had a positive TST, and 59 had both a positive QFT-GIT and TST. If a 5-mm threshold was used for all patients to determine TST positivity, then 254 patients would have a positive TST and 64 patients would have both a positive QFT-GIT and TST.

Across the 5 studies, 5 cases of active TB were reported by week 52 (Table 1). All 5 patients had a negative screening TST and negative IGRA results. There were no cases of active TB that developed among the 317 patients receiving golimumab and treated for latent TB with isoniazid (INH). Because the majority of cases of hepatotoxicity to INH therapy have generally occurred within the first 6 months, an evaluation of integrated safety data for signs of hepatotoxicity through week 24 is included.

Table 1. Cases of active TB across 5 GLM phase III studies through week 52*
StudyDiagnosisScreening TB test results/ BCG statusTB test results at time of diagnosisGLM dose, mg/no. of doses of GLMDemographicsTest resultsOutcome
  • *

    TB = tuberculosis; GLM = golimumab; RA = rheumatoid arthritis; MTX = methotrexate; IGRA = interferon-γ–release assay; TST = tuberculin skin test; CXR = chest radiograph; WNL = within normal limits; CS = corticosteroids; MRI = magnetic resonance imaging; AFB = acid-fast bacilli; CT = computed tomography; ILD = interstitial lung disease; AS = ankylosing spondylitis; LLL = left lower lobe.

  • Additional test results at the time of TB diagnosis.

GO-BEFORE: RA, MTX naiveBone TB of spine
  • IGRA: −

  • TST: − (0 mm)

  • CXR: WNL

  • BCG: + (at birth)

  • IGRA: +

  • TST: −

  • CXR: WNL

50/3
  • 64-yr-old white woman

  • Ukraine

  • Disease duration 7.4 yrs

  • No CS at baseline

  • MRI deformation of T8–T9 with spinal cord compression

  • Bone biopsy: granulomatous inflammation

  • Urinary and bowel incontinence resolved

  • Residual disability due to paresis

GO-BEFORE: RA, MTX naiveTB pleurisy
  • IGRA: −

  • TST: − (0 mm)

  • CXR: WNL

  • BCG: −

  • IGRA: −

  • TST: − (0 mm)

  • CXR: pleural effusion

100/11
  • 65-yr-old Asian woman

  • Philippines

  • Disease duration 1.4 yrs

  • Prednisone 7.5 mg daily at baseline

  • Thoracentesis: Gram stain, AFB, cytology (−)

  • CT scan: spiculated nodule

  • Pleural fluid culture at 42 days: −

Recovered
GO-BEFORE: RA, MTX naivePulmonary TB
  • IGRA: −

  • TST: − (5 mm)

  • CXR: ILD

  • BCG: −

  • IGRA: indeterminate

  • TST: + (>10 mm)

  • CXR: same as screening (ILD)

50/7
  • 67-yr-old Asian woman

  • Philippines

  • Disease duration 0.9 yrs

  • Prednisone 5 mg daily at baseline

  • Sputum smear: AFB × 3 (−)

  • Sputum culture: + for TB

Recovered
GO-FORWARD: active RA despite MTXTB pleurisy
  • IGRA: −

  • TST: − (15 mm)

  • CXR: WNL

  • BCG: + (age 12 yrs)

  • IGRA: +

  • TST: + (20 mm)

  • CXR: large pleural effusion

50/6
  • 38-yr-old Asian woman

  • Taiwan

  • Disease duration 13.7 yrs

  • Prednisone 5 mg daily, MTX 15 mg/week at baseline

  • Sputum for AFB (smear): −

  • AFB (culture): +

  • Pleural biopsy: nodular infiltration of lymphocytes and epithelioid histiocytes

Recovered
GO-RAISE: AS despite conventional treatmentPulmonary TB
  • IGRA: −

  • TST: − (3 mm)

  • CXR: WNL

  • BCG: + (age 4 yrs)

  • IGRA: +

  • TST: + (17 mm)

  • CXR: LLL infiltrate

100/10
  • 24-yr-old Asian man

  • South Korea

  • Disease duration 2 yrs

  • Prednisone 2.5 mg daily at baseline

  • Chest CT: highly suggestive of active TB

  • Serial AFB (smear and culture): −

Recovered

Additional case information.

Three cases of active TB were reported by week 52 in the GO-BEFORE study. In the first case, the patient developed TB in the thoracic spine. Her symptoms included back pain, paresis in the lower extremities, and urinary and bowel incontinence, which improved with anti-TB treatment. A retrospective medical history review after the TB diagnosis indicated that the patient had experienced back pain and had abnormalities in the thoracic vertebrae prior to study participation, which was attributed to vertebral compression fracture.

In the second case, the patient developed TB pleurisy. Symptoms included dyspnea, fever, and decreased breath sounds. Despite negative diagnostic tests, the patient improved with anti-TB medications, and therefore was considered to have TB infection.

In the third case, the patient had a screening chest radiograph that showed interstitial lung disease attributed to rheumatoid arthritis (RA). Symptoms included cough that worsened over a month. The chest radiograph was repeated and showed bronchiectasis with no new infiltrates. Approximately 1 month after initiation of TB treatment, a repeat chest radiograph showed chronic cystic changes and pulmonary TB. Three months after TB treatment was initiated, the repeat QFT result was negative.

A fourth case was TB pleurisy reported in a patient in the GO-FORWARD study. At screening, TST induration of 15 mm was considered negative according to local guidelines in Taiwan at the time of the study screening (INH treatment not required). Symptoms included chest pain, fever, cough, malaise, dyspnea, and weight loss. Approximately 9 months after starting treatment for TB, a chest radiograph showed inactive pulmonary TB lesions and minimal pleural effusion; a sputum culture showed no growth of TB bacilli.

A fifth case was reported in a patient in the GO-RAISE study. Symptoms included headache, fever, and rhinorrhea. The patient was treated for pulmonary TB and a chest radiograph performed ∼3 weeks later showed improvement.

Hepatotoxicity and treatment for latent TB infection.

Across all of the treatment groups, elevated ALT and AST values occurred in higher proportions of patients who were treated for latent TB infection versus those who were not (Table 2). The majority of ALT and AST elevations for both groups of patients (i.e., treated for latent TB infection or not treated for latent TB infection) were <3 times the upper limit of normal. Through 1 year of followup, 2 patients discontinued due to elevated liver tests related to INH; both were receiving placebo injections and discontinued prior to week 24.

Table 2. Proportion of patients by maximum ALT and AST through week 24 for patients with and without TB prophylaxis*
 PBO ± MTXGLM 50 mg ± MTXGLM 100 mg ± MTXGLM combined
  • *

    Values are the percentage unless otherwise indicated. ALT = alanine aminotransferase; AST = aspartate aminotransferase; TB = tuberculosis; PBO = placebo; MTX = methotrexate; GLM = golimumab; ULN = upper limit of normal.

  • Patients with results that are within the normal range (normal ranges: women, ALT 6–37 IU/liter and AST 10–36 IU/liter; men, ALT 6–48 IU/liter and AST 10–45 IU/liter).

Patients requiring TB prophylaxis, no.87101131232
 Patients with baseline ALT/AST ≤ULN, no.81/8295/98116/125211/223
  ≤ULN of ALT/AST67.9/74.451.6/66.365.5/84.859.2/76.7
  >1 to <2 × ULN of ALT/AST21.0/17.130.5/29.629.3/12.829.9/20.2
  ≥2 to <3 × ULN of ALT/AST3.7/3.711.6/4.13.4/1.67.1/2.7
  ≥3 to <5 × ULN of ALT/AST4.9/3.75.3/0.00.0/0.82.4/0.4
  ≥5 to <8 × ULN of ALT/AST1.2/1.21.1/0.01.7/0.01.4/0.0
  ≥8 × ULN of ALT/AST1.2/0.00.0/0.00.0/0.00.0/0.0
Patients not requiring TB prophylaxis, no.5475768411,417
 Patients with baseline ALT/AST ≤ULN, no.491/517535/558764/8081,299/1,366
  ≤ULN of ALT/AST79.0/88.672.5/82.475.9/85.974.5/84.5
  >1 to <2 × ULN of ALT/AST15.5/9.120.7/14.519.1/11.519.8/12.7
  ≥2 to <3 × ULN of ALT/AST2.9/1.94.1/1.42.1/1.12.9/1.2
  ≥3 to <5 × ULN of ALT/AST2.4/0.21.3/1.11.8/0.91.6/1.0
  ≥5 to <8 × ULN of ALT/AST0.2/0.21.1/0.40.4/0.10.7/0.2
  ≥8 × ULN of ALT/AST0.0/0.00.2/0.20.7/0.50.5/0.4

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

Reactivation of latent TB infection is a significant concern in the use of TNF inhibitors, and development of active TB in patients receiving anti-TNF therapy results in increased morbidity and mortality (5, 6). As previously reported, TB screening prior to biologic therapy reduces the incidence of reactivation of latent TB infection by up to 85% (5, 6). In an effort to reduce risk, a comprehensive TB screening program was employed in the Golimumab Phase III Program that included 3 TB screening tests (QFT-GIT, TST, and chest radiograph) along with close monitoring for the development of active TB. Use of an IGRA offered the potential of improved sensitivity in screening for latent TB; therefore, the IGRA (QFT-GIT) was added to the TST for patients enrolling in the golimumab studies. This strategy was developed because patient enrollment was expected to be high in countries where TB is endemic, and risk of active TB associated with TNF inhibitors has been shown to be much greater than the background incidence (5).

The 5 cases of active TB that were reported through 1 year all occurred in countries with high background TB rates. Two cases occurred in the Philippines, which has one of the highest TB incidence rates in Asia (290 per 100,000 in 2007; online at www.who.int/tb/country/data/download/en/index.html). The others occurred in Taiwan, South Korea, and Ukraine, which have incidence rates of approximately 70, 90, and 100 per 100,000, respectively, which are much higher than in the US (5.1 per 100,000 in 2007). Case 1 most likely represented progression of subclinical active disease not discovered by clinical screening, given the development of active TB within 3 months of initiation of golimumab and documented abnormalities in the spine prior to study entry. Case 4 also appears to be reactivation, given the development of active TB within 6 months of initiation of golimumab and the screening TST induration of 15 mm, which was considered negative by local country guidelines at the time; therefore, the patient was not treated for latent TB. Cases 2, 3, and 5 appear to be more consistent with new infection, since they occurred beyond 6 months after initiation of golimumab and were in TB-endemic areas. Because there is no gold standard test to distinguish between reactivated TB and new infection, this needs to be judged perhaps by examining case details and associated factors (i.e., the temporal association between active TB onset and initiation of treatment, and likelihood of new exposure). Whether detecting reactivation or new infection, especially in areas of high TB incidence, these 5 cases of active TB demonstrate the need for continued followup of patients regardless of TST and IGRA result at the time of starting biologic therapy.

Information about preventing reactivation of latent TB through more rigorous screening, detection, and subsequent treatment can be gleaned from comparisons of TB incidence data from other controlled studies with those of the Golimumab Phase III Program. In the Safety Trial for Rheumatoid Arthritis with Remicade (infliximab) Therapy (START) study (7), 7 of 1,082 patients developed active TB and 2 patients had reactivation of latent TB after receiving infliximab, despite screening with TST, chest radiograph, and careful evaluation of medical history. All 7 patients with active TB had a negative TST during screening and 3 of 7 patients had a fatal outcome (7). These results indicate the need to improve the sensitivity of screening methods to detect latent TB infection.

When comparing TB outcomes in the Golimumab Phase III Program versus the START study, our results suggest that by incorporating the IGRA, a nearly 3-fold lower incidence of active TB cases was observed in the Golimumab Phase III Program (5 [0.23%] of 2,171) compared with the START study (7 cases [0.66%] of active TB among 1,059 patients receiving infliximab), despite the substantial number of patients enrolled from Asia in the Golimumab Phase III Program versus none in the START study. No deaths attributed to TB infection occurred in the Golimumab Phase III Program through 1 year, whereas 3 of 7 patients who had TB in the START study died through 54 weeks of followup. This may imply that vigilant screening and surveillance in the Golimumab Phase III Program resulted in early detection of TB and initiation of anti-TB therapy, which ultimately prevented mortality.

In the Golimumab Phase III Program, 317 patients were diagnosed as having latent TB (by TST and/or IGRA) and were given INH simultaneously with golimumab therapy; none of the patients developed active TB through 1 year. In the START study, none of the 80 patients diagnosed as having latent TB during screening (by TST) and who received INH treatment simultaneously with infliximab developed active TB. In the golimumab clinical trials, compliance with treatment for latent TB was required by protocol. Studies have shown that many patients are not compliant with therapy in clinical practice (8), which reinforces that health care providers should remain vigilant for signs and symptoms of active TB both during and after completion of latent TB treatment.

Given that hepatotoxicity is a significant concern associated with the use of medications to treat latent TB, an analysis of maximum ALT and AST results through week 24 in the Golimumab Phase III Program was performed. The majority of elevations in ALT and AST observed were less than 3 times the upper limit of normal. These results are consistent with the results from a study of patients with RA, ankylosing spondylitis, and psoriatic arthritis who received INH to treat latent TB while receiving treatment with anti-TNF therapy (9).

In summary, 5 patients in the Golimumab Phase III Program were diagnosed with active TB through 1 year of followup despite having negative findings with the TST and QFT-GIT during screening. All 5 cases of TB occurred in highly TB-endemic areas, 3 of which were presumed to be primary infections and 2 of which were consistent with reactivation of latent TB. The comprehensive screening and followup measures used may have kept the number of active TB cases and associated mortality relatively low when considering the substantial numbers of patients enrolled from TB-endemic areas and the increased risk of active TB associated with TNF inhibitors. Despite multiple screening methods, physicians and the patients receiving anti-TNF therapies should watch closely for any signs and symptoms of TB, even when TB screening test results are negative.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Hsia 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 conception and design. Hsia, Matteson, Beutler, Hsu, Rahman.

Acquisition of data. Hsia, Matteson, Beutler, Doyle, Rahman.

Analysis and interpretation of data. Hsia, Cush, Matteson, Beutler, Doyle, Hsu, Xu, Rahman.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

This study was funded by Janssen Research & Development, LLC. The analyses were conducted by Janssen statisticians and programmers. All authors reviewed and approved the content of the manuscript before submission and jointly agreed to submit the final manuscript. The original studies for which the safety data were included in this integrated analysis were partially funded by Merck (formerly Schering-Plough), who had no role in this safety subanalysis or contribution to the content of this manuscript. Publication of this manuscript was not contingent upon the approval of Merck.

ADDITIONAL DISCLOSURES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

Dr. Doyle is currently employed by Alexion Pharmaceuticals, but was employed by Janssen Research & Development, LLC, at the time of the study. Dr. Rahman is currently employed by Pfizer, but was employed by Janssen Research & Development, LLC, at the time of the study.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES

The authors greatly appreciate the medical writing support of Mary Ann Thomas, RN, BSN, Mary Whitman, PhD, and Mary Ann Rittenhouse, RN, BSN, at Janssen Services, LLC.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
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