Early intervention in rheumatoid arthritis

Treatment must not only relieve symptoms but prevent bone erosion

Early treatment can curb the progression of rheumatoid arthritis (RA) and prevent deformities that occur due to bone erosion in the involved joint. "It is very crucial to recognize the disease very early," said rheumatologist Muhammad Asim Khan, professor of medicine at Case Western Reserve University in Cleveland, Ohio. "If left alone, it does lead to a lot of functional impairment as well as disability." Khan spoke in a symposium organized by Wyeth Philippines Inc. during the 14th annual convention of the Philippine Rheumatology Association in January.

    Various studies support the presence of bone erosion early on in the disease. Van der Horst-Bruinsma (1998), for example, showed that 25 percent of patients who consulted a rheumatologist for the first time already had erosions. Other studies showed between 60 and 93 percent of patients have bone erosions in one year.

    The risk of death also increases. Gabriel et al. (2003) wrote that RA patients have a 27-percent increased risk of dying compared with those without RA, and this is higher among women than men. "So the disease does shorten life span," pointed out Khan.

Proinflammatory proliferation

    Tumor necrosis factor alpha (TNFa) is a proinflammatory cytokine that plays an important role in diseases such as ankylosing spondylitis, psoriasis, Crohn's disease, and RA. Khan said that TNFa is "the conductor of the orchestra of inflammation: so if you do not have the conductor, the orchestra cannot play the music."

    Increased levels of TNFa lead to the typical manifestations of RA: inflammation, synovial pannus formation, cartilage breakdown, and bone resorption and erosions. It then makes sense that when TNF is blocked, there is control of symptoms, inhibition of joint-damage progression, and improvement in function.

    Newer drugs for RA are the so-called "biologic" disease-modifying antirheumatic drugs (DMARDs) that work by blocking various cytokine pathways. Examples of are infliximab, adalimumab, and etanercept. Etanercept (Enbrel) is a soluble human TNF receptor while infliximab and adalimumab are monoclonal antibodies. The current treatment strategy involves combining conventional DMARDs, usually methotrexate, with a biologic.

    Khan said that etanercept works by mimicking naturally occurring TNF receptors and inactivating TNF, thereby inhibiting the proinflammatory cascade. Administration of etanercept alone can provide reduction of disability as shown by Fleischmann et al. (2002). Health-assessment-questionnaire (HAQ) scores in patients with long-standing RA decreased from 1.6 to 1, but in patients with new-onset RA, HAQ scores decreased below 1.

    Several studies show that patients given etanercept, with or without methotrexate, respond consistently well, as measured by the criteria for disease-grade activity set by the American College of Rheumatology (ACR). "Exceeding ACR 20 is like jumping a hurdle that is 20 inches high and achieving ACR 50 is like jumping a hurdle that is 50 inches high." At ACR 70, the bar is at its highest, but at least 13 percent achieve this, which Khan described as an "outstanding response, almost like a remission."

    A study involving patients on etanecept monotherapy showed complete improvement in disease parameters. The number of swollen and tender joints also decreased dramatically during the treatment period. Patients on etanercept also had a decrease in their HAQ score and in level of C-reactive protein, a measure of inflammation.

    With regard to concomitant corticosteroid use, 41 percent stopped using steroids and 32 percent reduced steroid use. The average daily prednisone dose dropped from a baseline of seven mg to 2.5 mg after four years of etanercept use.

Monotherapy v. combination therapy

    In studies both etanercept and methotrexate showed sustained ACR responses, but etanercept appeared to benefit more patients at ACR 20 than methotrexate. Trials involving patients with early rheumatoid arthritis showed that 25 to 28 percent had normalization of HAQ score, but patients who were refractory to DMARDs and were then given etanercept did not react as well. Bathon et al. (2000) demonstrated that both etanercept and methotrexate effect a change in the Total Sharp Score, which indicates erosion.

    Meanwhile, the combination of etanercept and methotrexate was studied in the Trial for Etanercept and Methotrexate with radiographic Patient Outcome (TEMPO), a double-blind trial of 682 patients from Europe, Australia, and Israel.

    Results showed that the combination of etanercept and methotrexate increased the percentage of patients who achieved an ACR response over two years. "Combination therapy improves the outcome." In terms of disease-activity score, combination therapy showed greater mean improvement from baseline than monotherapy. "I hope you are convinced that the combination is the best treatment at the moment to prevent erosion, therefore resolving deformity," Khan said. M