Deactivation of vascular endothelium by monoclonal anti–tumor necrosis factor α antibody in rheumatoid arthritis

Objective. To assess whether monoclonal antibody to tumor necrosis factor α (TNFα) reduces endothelial activation in rheumatoid arthritis (RA). Methods. Levels of serum E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1), and circulating leukocytes (differential counts) were measured in RA patients before and up to 4 weeks after infusion of either placebo or chimeric anti-TNFα antibody cA2 (1 or 10 mg/kg). Results. Treatment with anti-TNFα decreased serum E-selectin and ICAM-1 levels, with the earliest detectable changes observed on days 1–3 after anti-TNFα infusion. No effect on VCAM-1 levels was detected. In parallel, there was a rapid and sustained increase in circulating lymphocytes. The extent of the decrease in serum E-selectin and ICAM-1 levels and the increase in lymphocyte counts was significantly higher (P ≤ 0.05) in patients in whom a clinical benefit of anti-TNFα was observed (≥20% response, by Paulus criteria, at week 4) compared with that in patients who failed to respond to anti-TNFα at this time point. Conclusion. We propose that decreased serum levels of adhesion molecules may reflect diminished activation of endothelial cells in the synovial microvasculature, leading to reduced migration of leukocytes into synovial joints, and thus prolonging the therapeutic effect of anti-TNFα in RA.     

Decrease in cellularity and expression of adhesion molecules by anti–tumor necrosis factor α monoclonal antibody treatment in patients with rheumatoid arthritis

Objective. The effect of chimeric anti–tumor necrosis factor α (TNFα) monoclonal antibody (MAb) therapy on synovial inflammation was studied in order to address the hypothesis that anti-TNFα therapy leads to down-regulation of adhesion molecules and a decrease in inflammatory cell influx in synovial tissue (ST). Methods. The immunohistologic features of synovial biopsy specimens, both before and 4 weeks after anti-TNFα MAb (cA2) therapy, were studied in 14 patients with rheumatoid arthritis (RA). The patients either received a placebo (n = 2), or were given intravenous doses of cA2 at 10 mg/kg (n = 5) or 20 mg/kg (n = 7). Results. A significant (P < 0.03) reduction in the mean scores for T cells and for the adhesion molecules, vascular cell adhesion molecule 1 and E-selectin, was observed after therapy with 10 mg/kg or 20 mg/kg of cA2 in RA patients. Conclusion. The reduced expression of adhesion molecules, and the decrease in cellularity of rheumatoid ST after cA2 administration support the hypothesis the antiinflammatory effect of anti-TNFα therapy might be partly explained by down-regulation of cytokine-inducible vascular adhesion molecules in ST, with a consequent reduction of cell traffic into joints.     

Outcomes after switching from one anti–tumor necrosis factor α agent to a second anti–tumor necrosis factor α agent in patients with rheumatoid arthritis: Results from a large UK national cohort study

Objective

Patients with rheumatoid arthritis (RA) who experience treatment failure with one anti–tumor necrosis factor (anti‐TNF) agent, due to either inefficacy or toxicity, are frequently switched to a second anti‐TNF agent, although the benefits of switching are unknown. The present study was undertaken to compare drug continuation rates between the first course and second course of anti‐TNF therapy.

Methods

The study involved a prospective cohort of RA patients from a UK national register of new anti‐TNF treatment starts (n = 6,739; 876 starting adalimumab, 2,826 starting etanercept, and starting 3,037 infliximab). Over a mean 15 months of followup, 841 patients stopped taking the first drug due to inefficacy and 1,023 stopped the first drug due to toxicity, of whom 503 and 353, respectively, were switched to a second anti‐TNF agent. Kaplan‐Meier survival curves were plotted to determine continuation rates for each course, and Cox regression was used to compare each course for the risk of stopping and the reason for stopping (inefficacy or toxicity).

Results

Overall, 73% of patients who switched to a second anti‐TNF agent remained on the new therapy by the end of followup. First drug discontinuation due to inefficacy was associated with an increased rate of second drug discontinuation due to inefficacy (hazard ratio [HR] 2.7, 95% confidence interval [95% CI] 2.1–3.4) but not toxicity (HR 1.1, 95% CI 0.9–1.5). Similarly, first drug discontinuation due to toxicity was associated with an increased rate of second drug discontinuation due to toxicity (HR 2.3, 95% CI 1.9–2.9) but not inefficacy (HR 1.2, 95% CI 0.8–1.6).

Conclusion

RA patients who are switched to a second anti‐TNF drug have high rates of continuation, although among those who must discontinue treatment, the reasons for stopping a second drug are related to the reasons for stopping the first drug. This large data set from the UK provides the first estimates of the magnitude of these effects in patients with long‐standing severe RA.

     

Serious infection following anti–tumor necrosis factor α therapy in patients with rheumatoid arthritis: Lessons from interpreting data from observational studies

Objective

In a recent observational study, we found that the risk of serious infection following anti–tumor necrosis factor α (anti‐TNFα) therapy in patients with rheumatoid arthritis (RA) was not importantly increased compared with the background risk in routinely treated RA patients with similar disease severity. Observational data sets are, however, subject to a number of important biases related to selection factors for the timing of starting and stopping therapy. Infection risk is also likely to vary with duration of therapy. This study was undertaken to examine the influences of these biases and of the method of analysis on the risk of infection.

Methods

We compared the risk of serious infection in 8,659 patients treated with anti‐TNFα with that in 2,170 patients treated with traditional disease‐modifying antirheumatic drugs (DMARDs) recruited to the British Society for Rheumatology Biologics Register. We applied a number of statistical models in which we varied the length of the followup period by using different definitions of the date of discontinuation of treatment and different lag periods of risk following drug cessation.

Results

When the at‐risk period was defined as “receiving treatment”, the adjusted incidence rate ratio comparing patients receiving anti‐TNFα therapy with patients receiving DMARD therapy was 1.22 (95% confidence interval [95% CI] 0.88–1.69). Limiting followup to the first 90 days, however, revealed an adjusted incidence rate ratio of 4.6 (95% CI 1.8–11.9). Rates of infection were increased in the 90 days immediately following drug discontinuation and beyond, explained by selection factors for drug discontinuation.

Conclusion

These findings show that overall, the way in which UK rheumatologists select patients for starting and discontinuing anti‐TNFα therapy explains our previous finding of no increase in risk. However, there may be important increases in true risk, notably early in the course of treatment, that would become more evident depending on the definition of at‐risk period.

     

Demyelination occurring during anti–tumor necrosis factor α therapy for inflammatory arthritides

Objective

To review the occurrence of neurologic events suggestive of demyelination during anti–tumor necrosis factor α (anti‐TNFα) therapy for inflammatory arthritides.

Methods

The Adverse Events Reporting System of the Food and Drug Administration (FDA) was queried following a report of a patient with refractory rheumatoid arthritis who developed confusion and difficulty with walking after receiving etanercept for 4 months.

Results

Nineteen patients with similar neurologic events were identified from the FDA database, 17 following etanercept administration and 2 following infliximab administration for inflammatory arthritis. All neurologic events were temporally related to anti‐TNFα therapy, with partial or complete resolution on discontinuation. One patient exhibited a positive rechallenge phenomenon.

Conclusion

Further surveillance and studies are required to better define risk factors for and frequency of adverse events and their relationship to anti‐TNFα therapies. Until more long‐term safety data are available, consideration should be given to avoiding anti‐TNFα therapy in patients with preexisting multiple sclerosis and to discontinuing anti‐TNFα therapy immediately when new neurologic signs and symptoms occur, pending an appropriate evaluation.

     

Detection of tumor necrosis factor α but not tumor necrosis factor β in rheumatoid arthritis synovial fluid and serum

Synovial fluids from 6 of 12 patients with rheumatoid arthritis (RA) and from 3 of 11 patients with reactive arthritis contained measurable levels of tumor necrosis factor α (TNFα). Seven of 12 sera from RA patients contained TNFα, while only 1 of those from reactive arthritis patients was positive. Gamma-inter-feron was detected in the synovial fluids and sera of only the RA patients. Tumor necrosis factor β was not detected in any sera or synovial fluids. RA patients with detectable TNFα had higher erythrocyte sedimentation rates and synovial fluid leukocyte counts.     

Eligibility of patients in routine care for major clinical trials of anti–tumor necrosis factor α agents in rheumatoid arthritis

Objective

To identify the proportion of patients with rheumatoid arthritis (RA) in 2 cohorts from Nashville, Tennessee, who met basic criteria for inclusion in 2 important recent clinical trials of anti–tumor necrosis factor α (anti‐TNFα) agents, the early RA (ERA) trial of etanercept versus methotrexate, and the anti‐TNFα trial in RA with concomitant therapy (ATTRACT) study of infliximab plus methotrexate versus methotrexate.

Methods

Two cohorts of patients, all of whom had met the American College of Rheumatology criteria for RA at some time, were studied. Cohort E (early) comprised 232 patients who were under the care of 5 private practice rheumatologists, whose duration of RA was fewer than 3 years, and who were reviewed for basic inclusion criteria for the ERA clinical trial. Cohort L (long‐term) comprised 152 consecutive patients who had been under care at a weekly academic rheumatology clinic for a mean of 4.5 years, and were reviewed for basic inclusion criteria for the ATTRACT study.

Results

In cohort E, basic inclusion criteria for the ERA trial were met by 11 of 36 patients (31%) who had not taken methotrexate, 8 of 19 patients (42%) who were at their first visit and had not taken methotrexate, and 37 of all 232 patients (16%). In cohort L, 5% of patients met the basic inclusion criteria for the ATTRACT study.

Conclusion

Most patients who were seen in routine care in these 2 cohorts did not meet the criteria for inclusion in these 2 important recent clinical trials. The conclusion that anti‐TNFα therapy has greater efficacy than methotrexate may be valid only in a limited number of patients with the most severe RA. Anti‐TNFα therapy may be desirable in most patients with RA, but this possibility has not been studied formally. Criteria for inclusion in RA clinical trials might be modified for greater generalizability of results.