« Back

Treatment expectations with TNF inhibitors

Wednesday, December 12 2007 | Comments

---

What's This? The use of tumor necrosis factor inhibitors in patients with rheumatoid arthritis can help slow or prevent joint destruction, which can occur even when disease activity is low, and may increase productivity and quality of life if used appropriately, according to a panel of experts.

Clinical remission of RA in addition to clinical improvement is the aim of treatment because even in situations of low disease activity there is progression of joint destruction, according to Dr. Josef Smolen, chairman of the division of rheumatology at the Medical University of Vienna.

"RA is governed by functional impairment," which is a consequence of the inflammatory process and the accrued joint damage, he noted, adding that only disease remission can halt joint damage progression.

Both active disease and joint damage are associated with disability. Although disease activity can be reversed, "the irreversible component [of the disease] is a consequence of joint damage," Dr. Smolen said.

When there is low disease activity, there is progression of joint damage, even when a traditional disease-modifying antirheumatic drug, such as methotrexate, is used. However, methotrexate in combination with a TNF inhibitor appears to significantly impede joint damage irrespective of disease activity. Further, patients in remission have somewhat better outcomes than do patients with high disease activity, even with combination therapy.

In addition, achieving a response to therapy, such as American College of Rheumatology responses, may not be meaningful if low disease activity or remission is not demonstrated, according to Dr. Smolen. Therefore, composite disease activity indices are more meaningful as they allow for the calculation of absolute disease activity and allow for the categorization of disease activity status. These composite indices include the Disease Activity Score (DAS), the DAS including a 28-joint count (DAS28), the Simple Disease Activity Index, and the Clinical Disease Activity Index.

Dr. Smolen noted that the disease status at 1 year can be predicted within 3 months of starting therapy, "so remission is the goal."

"If we change our expectations, we can make a difference," Dr. Smolen added.

According to Dr. Paul Emery, clinical director of rheumatology at the Leeds Teaching Hospitals Trust and University of Leeds, joint damage occurs in 70% of the patients within the first 3 years after symptom onset.

The joint damage continues to progress during the patient's lifetime and results in functional decline, disability, poor QOL, and loss in work productivity.

Therefore, the optimal treatment of RA requires early recognition of the disease, and effective therapy should reduce synovitis and inhibit radiographic progression of the disease, Dr. Emery noted.

Recent data have shown that bone destruction may be caused by the promotion of osteoclastogenesis and osteoclast activation by TNF, he stated, adding that TNF inhibitors appear to reduce synovitis and slow or prevent radiographic progression of RA.

According to Dr. Emery, TNF antagonists have been shown to hinder progression in Total Sharp Scores over time more effectively than do conventional DMARDS or other biologic therapies that do not block TNF.

Increasingly, work outcomes are being used to measure the effectiveness of therapies as work loss occurs very quickly among patients with RA, Dr. Emery said. For example, approximately 20% of patients with RA experience work disability within the first year. This increases to 32% to 50% after 10 years and up to 90% after 30 years.

However, treatment with TNF antagonists has been shown to benefit work productivity. Specifically, patients with RA who were treated with methotrexate in combination with infliximab or etanercept maintained their employment longer and remained more employable as compared with patients who received methotrexate alone. In addition, data from the DE032 trial showed that adalimumab-treated patients who also received methotrexate had significantly fewer days lost from work and significantly higher presenteeism as compared with those who received methotrexate alone.

"Work productivity for a rheumatoid patient is a fantastically sensitive measure," he stated. "If you've got inflamed joints [and] are stiff in the morning, it really is quite a challenge to get yourself out of bed, ready for work, make sure you turn up, and produce a normal day's work."

When deciding whether to treat a patient with TNF inhibitors, the benefits of the treatment should be balanced against the risks, according to Dr. Arthur Kavanaugh, director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego School of Medicine.

Some of the benefits of TNF inhibitors include the ability to substantially improve the signs and symptoms of RA, to optimize QOL and functional status, and to prevent joint damage progression. Some of the risks associated with these therapies include infections, malignancies, demyelinating conditions, hematologic abnormalities, and skin reactions.

As more than 1.5 million patients have been treated with TNF inhibitors, much has been learned about the range of toxicities and key predisposing characteristics. Therefore, strategies have been developed to minimize toxicity sequelae.

For instance, Dr. Kavanaugh noted the SAFETY strategy, which stands for stratify, assess, fend-off, evaluate, treat, and yearly. Specifically, he said patients should be stratified according to their comorbidities, medications, age, and so on. They should also be assessed for hepatitis B and C status, tuberculosis status, and vaccination status. Fend-off refers to vaccinations and optimizing health. Physicians should evaluate expected adverse events and treat AEs aggressively. Finally, the patient should be re-evaluated yearly.

Depending on the patient demographics, comorbidities, disease characteristics, and other medications the patient is taking, "the benefit [of TNF inhibitors] does indeed outweigh the risks," Dr. Kavanaugh concluded.

By Nancy Stanley

Print  |  E-mail