Use of the T-SPOT.TB assay to detect latent tuberculosis infection among rheumatic disease patients on immunosuppressive therapy.

OBJECTIVE: We evaluated the T-SPOT.TB assay to identify latent tuberculosis infection (LTBI) in patients with rheumatic disease receiving immunosuppressive medication including tumor necrosis factor (TNF) antagonists. METHODS: A total of 200 patients seen in the Arthritis Center at Brigham and Women's Hospital were enrolled for study. Most patients were US-born women with rheumatoid arthritis. A medical history was obtained using a questionnaire, whole blood was drawn for the T-SPOT.TB assay, and tuberculin skin testing (TST) was performed. RESULTS: Both tests were performed on 179 subjects, who had no history of a positive TST. All subjects had a strong response to the T-SPOT.TB test positive control, and there were no indeterminate results. Among these 179 subjects, 2 had a positive TST and 10 had a positive T-SPOT.TB test. No subject was positive for both tests. Patients with a positive T-SPOT.TB test did not have typical risk factors for LTBI based on clinical evaluation. CONCLUSION: The lack of concordance between the TST and the T-SPOT.TB assay may indicate that the immunoassay is more sensitive, particularly in a patient population taking immunosuppressive medications. It is equally likely that the low prevalence of LTBI in this low-risk population led to an increase in the false-positive rate despite the high sensitivity and specificity of the T-SPOT.TB assay. In the context of our patient population, the T-SPOT.TB assay is likely to be most useful in evaluation of patients with a positive TST, since these patients have a higher pretest probability of having LTBI.

Peripheral blood expression of nuclear factor-kappab-regulated genes is associated with rheumatoid arthritis disease activity and responds differentially to anti-tumor necrosis factor-alpha versus methotrexate.

OBJECTIVE: To evaluate peripheral blood expression of genes regulated by nuclear factor-kappaB (NF-kappaB), a key mediator of tumor necrosis factor-alpha (TNF-alpha) signaling, in patients with rheumatoid arthritis (RA) before and during treatment with anti-TNF-alpha or methotrexate (MTX). We analyzed association of gene expression with disease activity, rheumatoid factor (RF), age, sex, disease duration, treatment modality, and clinical response. METHODS: Sixty patients consented for RNA analysis at baseline and after 2 and 6 weeks of treatment. Disease activity was quantified using Disease Activity Score (DAS28) and C-reactive protein (CRP). Expression of 67 TNF-alpha-responsive, NF-kappaB-regulated genes was measured using Affymetrix arrays and RT-PCR. RESULTS: Expression of 34 genes was associated with DAS28-CRP, notably S100A12/calgranulin C, IL7R, and aquaporin 3. No association was observed with age, sex, RF, or disease duration. Expression of 16 genes changed in a manner that differed significantly between treatment groups. Eleven were reduced in anti-TNF-alpha-treated patients relative to MTX, while 5 were increased. The majority of these observations were confirmed using RT-PCR. Gene expression was not associated significantly with change in disease activity. CONCLUSION: NF-kappaB-dependent gene expression in peripheral leukocytes is highly correlated with RA activity as measured by DAS28-CRP. Expression of many genes responds differentially to anti-TNF-alpha versus MTX, suggesting fundamentally different effects on the NF-kappaB pathway. This peripheral blood expression signature provides candidate markers that could lead to development of a simple, minimally invasive pharmacodynamic assay for RA treatments directed at the NF-kappaB pathway. Combination of gene expression data with clinical scores and serum markers may provide more sensitive and predictive measures of RA disease activity.

Comparison of 2 doses of etanercept (50 vs 100 mg) in active rheumatoid arthritis: a randomized double blind study.

OBJECTIVE: To assess the safety and efficacy of etanercept 50 mg administered twice weekly versus 25 mg administered twice weekly as monotherapy in patients with tumor necrosis factor-alpha (TNF-alpha) blocker-naäve active rheumatoid arthritis (RA). METHODS: Seventy-seven patients with RA were randomized in an unequal allocation (2:1) in a blinded fashion to receive either 50 mg (51 patients) or 25 mg (26 patients) of etanercept twice a week for 24 weeks. RESULTS: The primary outcome measure, the ACR-N AUC at 24 weeks, showed no difference between the 2 dose groups. In addition, there was no difference in ACR 20, 50, and 70 responses or in EULAR response criteria by Week 24. There were no statistically significant differences between the 2 groups in the proportion of patients with any non-infectious adverse event. The proportion of patients with upper respiratory tract infections was significantly higher in patients receiving 50 mg etanercept compared with those receiving 25 mg (26% vs 4%, p = 0.027). CONCLUSION: Etanercept as a monotherapy at 50 mg twice weekly does not provide increased efficacy when compared to the standard dose of 25 mg twice weekly in TNF-alpha blocker-naäve patients.

Pattern of infliximab utilization in rheumatoid arthritis patients at an academic medical center.

OBJECTIVE: To investigate the pattern of use of infliximab with an emphasis on treatment escalation and the durability of infliximab use in the management of rheumatoid arthritis (RA) in an academic setting. METHODS: We conducted a retrospective review of pharmacy and medical records of 183 patients with RA who received at least 1 infliximab infusion at the infusion centers of the Brigham and Women's Hospital. Treatment escalation was defined as an increase in the dosage of infliximab to >3 mg/kg and/or a decrease in the dosing interval to <7 weeks between infusions. RESULTS: A total of 183 patients with RA received infliximab infusions for a mean +/- SD duration of 58.2 +/- 56.6 weeks. Infliximab was discontinued in 48% of the patients during the first year of therapy and in 67% of the patients overall. A total of 126 patients had a treatment escalation, including 25 patients with a dose increase, 35 patients with a decrease in the interval, and 66 patients with both. Infliximab treatment was associated with a decrease in corticosteroid and methotrexate doses. Patients who had a treatment escalation were more likely to continue infliximab infusions compared with patients without a treatment escalation (odds ratio 2.0, 95% confidence interval 1.0-4.1). CONCLUSION: The use of infliximab may be an effective treatment for RA; however, a substantial number of patients will discontinue its use. Treatment escalation is commonly used in the management of RA with infliximab and is associated with longer duration of infliximab use.

Etanercept in the treatment of adult patients with Still's disease.

OBJECTIVE: To evaluate the safety and efficacy of etanercept in the treatment of adult patients with Still's disease. METHODS: Twelve adult patients who met criteria for Still's disease and had active arthritis were enrolled in a 6-month open-label trial of etanercept given in biweekly doses of 25 mg. The mean disease duration at study entry was 10.7 years. All patients had been treated unsuccessfully with other disease-modifying antirheumatic drugs. Efficacy was evaluated according to American College of Rheumatology (ACR) improvement criteria, and adverse events were recorded. RESULTS: Ten patients successfully completed the study; 2 withdrew due to disease flare. In 4 patients, the dosage of etanercept was increased from 25 mg biweekly to 25 mg 3 times per week. Seven patients met ACR 20% response criteria. Of these 7 responders, 4 met ACR 50% response criteria and 2 met ACR 70% response criteria. Among the 3 patients with systemic features of Still's disease (fever and rash), improvement in these features was seen in 1; the arthritis did not improve in any of these 3 patients. Except in the 2 patients who withdrew due to disease flare (rash, fever, and arthritis), no other significant adverse events occurred. CONCLUSION: In this initial study of etanercept therapy for Still's disease in the adult, this treatment resulted in improvement in the arthritis and was well tolerated. Additional trials should be performed to elucidate the effects of tumor necrosis factor inhibitors in Still's disease.