Etanercept (Enbrel®) is a new disease modifying antirheumatic drug (DMARD), precise and specific in its location of action, used to treat RA and AS, a rheumatic disease that causes arthritis of the spine and sacroiliac joints and can cause inflammation of the eyes, lungs, and heart valves. In RA, etanercept can be used in combination with other DMARDs or other therapies so as to achieve more significant disease arrest. In AS, etanercept is emerging as a possible therapeutic option that significantly improves AS disease activity.

Etanercept is given in the form of a subcutaneous injection 2 times a week and was originally approved for moderate-to-severe RA pain previously unresponsive to at least 1 other DMARD. Results of the etanercept use in Early Rheumatoid Arthritis (ERA) trial have shown that etanercept can be used as first line therapy, for the mild-to-moderate RA pain. Although the cost of etanercept can be viewed as somewhat prohibitive-a 1-month supply can cost up to $1,100-patients taking etanercept have reported rapid clinical improvement. Immunomodulating therapies such as etanercept offer a greater chance of achieving disease remission is the ultimate goal of rheumatic therapy.

Etanercept vs. Methotrexate (MTX) in Early Rheumatoid Arthritis (ERA) Trial: Two-Year Follow-Up

In the first year of a 2-year investigation of patients with RA (mean disease duration = 1 year), etanercept 25 mg twice weekly resulted in a more rapid clinical response and was more effective in preventing erosions than high dose 20 mg per week methotrexate (Arthritis & Rheumatism 1999;42:S117).

In an open-label extension (2nd year) of this Immunex-sponsored ERA trial, investigators demon-strated that in patients with early erosive rheumatoid arthritis, 25 mg etanercept twice weekly effectively reduced clinical signs and symptoms of RA and prevented radiographic progression for at least 2 years.

Of the patients who initially received etanercept, 75% (155 of 207) completed treatment. Of the patients who initially received methotrexate, 58% (126 of 217) completed 2 years of treatment. Additionally, twice as many patients (12%) discon-tinued methotrexate due to adverse events as com-pared to those patients taking etanercept.

Adverse events occurring in patients in the methotrexate arm included nausea, mouth ulcers, and hair loss (> 10%). Lung toxicity also occurred (2%). In contrast, the only adverse event reported in etanercept-treated patients was injection site reaction (> 10%).

The rate of infection was higher for methotrexate (1.70 vs. 1.39 events per patient per year, p < 0.001), but there were no opportunistic infections or infection-related deaths in either arm. Hematologic abnormalities were higher for methotrexate than for etanercept.

An ACR20 response, which is defined as a 20% or more improvement in tender joint count, was seen in 80% of patients initially randomized to etanercept and in 62% of those initially randomized to methotrexate (p = 0.005). An improvement in the health assessment questionnaire disability score of =0.5 was seen in 55% of etanercept-treated patients versus 37% of methotrexate-treated patients (p < 0.001).

In an analysis of 2-year X-ray data of 254 patients, total Sharp score progression and erosions were more pronounced in the methotrexate-treated group. Median change in total Sharp scores over 2 years was 3.2 for methotrexate versus 1.3 for etaner-cept (p = 0.001). With longer exposure, etanercept continues to be well tolerated.

The change in joint erosion scores was significant (1.9 versus 0.7, respectively; p = 0.001), and was lower-but not significantly so-for joint space narrowing (1.3 versus 0.7, respectively).

One Year Community-Based Experience with Etanercept in the Treatment of Rheumatoid Arthritis

Community-based experiences with new drugs can provide insight into the efficacy and safety parameters one might expect in clinical practice versus what might be reported in clinical trials. In one such experience with etanercept, clinicians from a community center in Portland, Maine reported on their first 89 adults patients with rheumatoid arthritis who were treated and followed for 1 year or more.

In their experience, etanercept seemed effective and well tolerated, Marc Miller, MD, said, even among patients who had longstanding disease that previously had not responded to multiple DMARDs. The patient population included 71 women and 18 men (average age = 55 years; average disease duration = 14 years), of whom 37% had severe rheumatoid arthritis. Prior to treatment with etanercept, patients had taken an average of 4.4 DMARDs.

The overall response rate was 83%, and approximately 3/4 of these patients (73%) were still taking etanercept at 1 year, according to Dr. Miller. Discontinuations were primarily due to inefficacy (17%), while the rest discontinued because of adverse effects-related or unrelated to treatment- including cough, diarrhea, lymphoma, pregnancy, and "needle phobia." One patient discontinued due to the expense of the drug.

Of the 65 patients still taking etanercept at 1 year, almost half (42%) were taking other DMARDs as well. Swollen joint count for these patients at 1 year was 2.2, down from 8.5 before treatment, and aver-age prednisone dose decreased from 5.1 mg to 2.0 mg per day.

According to the investigators, 57% had an "excellent" response to etanercept, while 43% had a partial response to treatment, which was adequate to continue on etanercept. "There were no significant adverse affects in the group continuing therapy," Dr. Miller concluded.

Etanercept in the Treatment of Ankylosing Spondylitis: A Randomized, Double- Blind, Placebo-Controlled Study

Evidence that TNF-alpha plays a role in spondyloarthropathy and ankylosing spondylitis has led to investigations of anti-TNF agents such as infliximab (Remicade®) and etanercept in these diseases. Initial data from one notable study, supported by Immunex, suggests that in moderate to severe anky-losing spondylitis, etanercept significantly improves outcome measures such as morning stiffness, spinal pain, and swollen joint count, as well as Bath Ankylosing Spondylitis Functional Index (BASFI) scores.

While the 4-month randomized portion of the study is not yet completed- projected enrollment is 40 patients-complete data from the initial double-blind, placebo-controlled study was available for 11 patients, and all 11 patients have continued on the 6-month open-label extension of the study were available for presentation at ACR 2000. Seven of these patients have completed the open- label extension phase, and all have responded to etanercept therapy.

The open-label extension data showed that most patients had an ACR20 response, while more than three-quarters had an ACR50 response (defined in a similar manner as ACR20, but with improvement of at least 50% in the individual measures, respectively), and more than half had an ACR70 response (defined in a similar manner as ACR50, but with improvement of at least 70% in the individual measures, respectively), with improvement reaching statistical significance for BASFI, pain, and morning stiffness.

There have been 19 adverse events in the open-label phase, including 10 injection site reactions, and 3 uncomplicated infections. There have been no serious adverse events, though "the open label design of this study demands critical assessment of our results," said Jennifer Gorman, MD.

Conclusion

It appears that etanercept is an effective and well-tolerated treatment for RA and in patients with longstanding disease previously unresponsive to multiple other DMARDs. It has been shown that etanercept effectively reduces the clinical signs and symptoms of RA and also effectively prevents radiographic progression for at least 2 years. As demonstrated in the open label extension, etanercept may significantly improve disease activity in AS. The completion of the double-blind, placebo-controlled study on the use of etanercept will advance current knowledge of TNF-alpha inhibitors in the treatment of rheumatic disease.