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Humira is being tested for ankylosing spondylitis.
More biologics are emerging to treat the esoteric condition known as ankylosing spondylitis (AS), a chronic, progressive autoimmune condition. AS is primarily characterized by inflammation in the axial skeleton, peripheral joints, and enthesis (the site of ligamentous attachment to the bone). AS most commonly strikes individuals between the ages of 20 and 40, and affects men approximately three times more often than women.
"This disease is more common than we previously thought," stated John C. Davis, M.D., a rheumatologist at the University of California at San Francisco. "Patients with AS can experience a range of clinical symptoms from occasional back pain to a chronic and progressive form of the disease that attacks the spine and other organs. This can often result in loss of motion and deformity as well as have a devastating impact on a patient's quality of life," he added.
Over the past few decades, treatment of AS has consisted mainly of nonsteroidal anti-inflammatory drugs (NSAIDs) and physiotherapy. NSAIDs are often effective in diminishing pain and stiffness; however, these agents fail to modify disease course or control disease activity. Second-line immunosuppressive drugs such as sulfasalazine may be effective in early and active AS with peripheral arthritis, but their role in treating severe AS or disease with spinal involvement has not been so promising.
Increasing evidence from published literature now suggests that tumor necrosis factor a (TNF-a), a proinflammatory mediator, may play a role in the pathogenesis of AS. So biological agents that block TNF-a appear to be the emerging treatment options that just might change the course of this destructive disease. Currently in the United States, etanercept (Enbrel, Amgen and Wyeth) is the only Food & Drug Administration-approved TNF-a antagonist available for the treatment of AS.
Evidence-based guidelines for the use of anti-TNF-a therapy in patients with AS were developed by the Assessments in AS (ASAS) Working Group and published in the Annals of Rheumatic Diseases in 2003. The authors recommend etanercept and infliximab (Remicade, Centocor) for the treatment of active AS in patients who have failed conventional therapy.
Davis, who is also one of the authors of the Annals article, explained that "before initiating these TNF-a antagonists, a failure of NSAID treatment for at least three months is required for all three presentations of ASaxial disease, peripheral arthritis, and enthesitis." The authors of the guidelines further recommend that for symptomatic peripheral arthritis, treatment failure with intra-articular corticosteroids and sulfasalazine is required before initiation of TNF-a antagonists. In addition, patients with symptomatic enthesitis should receive an adequate trial of at least two local steroid injections before initiating anti-TNF therapy.
If first-line treatment options have failed, said Davis, "I usually treat my patients for six to eight weeks with a TNF-a antagonist." He said he has treated approximately 100 patients with AS.
Several well-designed clinical trials have evaluated the efficacy of anti-TNF agents in patients with AS. In a study published in Arthritis & Rheumatism in 2003, treatment with etanercept twice weekly for 24 weeks proved to be highly effective and was well tolerated in AS patients. At the end of the study period, 57% of the patients receiving etanercept demonstrated significant improvement in the validated composite measure, the ASAS20, compared with 22% of the patients in the placebo group. The striking aspect of the study results was that improvements in response criteria were seen as early as two weeks after therapy initiation.
The authors of a previous study in Arthritis & Rheumatism in 2001 documented their remarkable findings that after patients received etanercept therapy, resolution of entheseal abnormalities in the spine was observed, as determined by magnetic resonance imaging (MRI).
The efficacy and safety of infliximab therapy in AS patients was evident in a trial published in the Annals of Rheumatic Diseases in 2003. Patients received intravenous infliximab at a dose of 5 mg/kg at weeks 0, 2, 6, and every eight weeks thereafter for 12 months. The primary endpoint, a reduction of the patient's global assessment of pain (GAP) by > 20%, was achieved in 92% of the subjects. Infliximab is currently awaiting FDA approval for the treatment of AS.
Besides etanercept and infliximab, what other TNF-a antagonists are currently being evaluated for the treatment of this disabling condition? Abbott Laboratories recently announced the initiation of a global phase III study evaluating the potential of adalimumab (Humira) in treating AS. Currently, adalimumab has an FDA-approved indication for reducing signs and symptoms and inhibiting the progression of structural damage in patients with rheumatoid arthritis. In this forthcoming trial, AS patients who have had an inadequate response to NSAIDs will be randomized to receive either adalimumab or placebo. Patient response in this study will be measured by improvements in signs and symptoms, disease progression, and quality of life.
"We hope this trial will yield information about whether Humira will be an option in reducing the severe joint and back pain that affects AS patients," said James B. Lefkowith, divisional VP, Immunology Development, Abbott Laboratories.
Clinicians involved in the care of AS patients are anticipating the results of such a pivotal study, hoping that the evidence will sway toward the likelihood that "the use of anti-TNF therapy will actually halt the AS disease process," noted Davis, co-lead investigator of the study.