Four new studies provide insight into how and when to utilize disease modifying anti-rheumatic drugs (DMARDs), biologics, and non-steroidal anti-inflammatory drugs (NSAIDs) in ankylosing spondylitis (AS).

One study examined 42 active AS patients treated with methotrexate (MTX) who were randomly assigned to receive five infusions of either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22.¹ It was reasoned that concomitant treatment with MTX would allow for a maintenance dosing interval of 8 weeks, longer than the 6-week interval recommended by recent guidelines for anti-TNF-α monotherapy in AS. A significantly greater improvement in mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score occurred in the infliximab arm at week 10 compared to the placebo arm, however disease flares were reported by some patients on infliximab at week 30, 8 weeks after the last infusion. Both agents were well tolerated with no dropouts due to adverse events

Evaluation by MRI revealed that the mean number of lesions that resolved per patient from week 0 to week 30 was significantly greater in the combination group than in the MTX monotherapy group, the study showed.

"From this preliminary study, the major finding was that it was not possible to increase the interval between infusions by the use of MTX, although there was some evidence that methotrexate did have a positive effect on reduction of side effects, and perhaps on efficacy," says lead author Paul Emery, MD, MA, professor of rheumatology and clinical director of Leeds Teaching Hospitals Trust in the United Kingdom.

 

Etanercept results at 2 years

In an open-label extension of a 24-week randomized controlled trial,² etanercept provided sustained durability of response in improving signs and symptoms of AS for nearly 2 years. Patients received 25 mg twice weekly subcutaneous etanercept for up to 72 weeks, resulting in 96 weeks of cumulative exposure for those randomized to the active arm of the initial trial. Among patients in this group, 74% achieved an Assessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks, the study showed.

Patients initially randomized to placebo demonstrated similar responses, with 78% achieving an ASAS 20 response after 72 weeks of etanercept therapy. Patients in both groups demonstrated improved spinal mobility, and the therapy appeared to be well-tolerated in patients treated for up to 96 weeks.

"We believe that the improvement of spinal mobility is an especially promising effect of etanercept treatment; imaging studies may shed more light on the effect of etanercept on structural damage," conclude researchers led by John C. Davis, MD, assistant professor of rheumatology at the University of California, San Francisco.

"This study shows that patients taking etanercept for AS get dramatically better and don't have deterioration," says Gilbert Kepecs, MD, chief of rheumatology at Hackensack University Medical Center in Hackensack, New Jersey.

He points out that anti-TNF-α agents are the first drugs to be shown to reduce inflammation and prevent progression of the disease, and that "all the data over the last 2 years have dramatically changed how we do things."

TNF-α inhibitors "have already become the standard of care [and] most people with diagnosis of AS should be started on them as soon as possible," he says. As of today, etanercept and infliximab are the only TNF-α inhibitors that are approved for the treatment of AS, although adalimumab is also prescribed off-label.

Older AS treatments had much more severe side effects than biologics, Dr. Kepecs explains. "The toxicity for infliximab and etanercept looks significant, but in practice it's very rare," he says. "It is miniscule in postmarketing studies."

Dr. Kepecs suggests that the some of the reported adverse effects of TNF-α inhibitors may not be of great concern. "We have not seen an increase of infection, with the possible exception of tuberculosis, and we screen for it; if it's not present than it's not a risk," he says. "Lymphoma risk tends to spook people and numbers have been thrown around, but people with severe RA have increased risk of lymphoma. If there is an increased risk, it is small, and it's likely that there is no increased risk"

 

NSAID therapy are more effective in AS patients without peripheral disease

A recently published paper from Annals of the Rheumatic Diseases reports on a post-hoc subgroup analysis of a 6-week trial in which 387 patients with active axial AS were randomized to receive 90 mg or 120 mg of etoricoxib once daily, naproxen 500 mg twice daily, or placebo.³ All patients in active arms demonstrated a significant treatment response versus placebo for all efficacy measures, and this held true in patients with and without peripheral arthritis. However, the difference in patients' assessment of spine pain between the active and placebo treatments was significantly greater among patients without peripheral arthritis when compared to those with peripheral symptoms.

"NSAIDs and COX-2 inhibitors have a clinically relevant symptomatic effect on axial AS irrespective of the presence of peripheral arthritis," conclude researchers led by L. Gossec, MD, of the René Descartes University and Cochin Hospital in Paris, France. "However, in this exploratory analysis, spinal improvement appears greater in patients without peripheral disease."

 

Continuous versus intermittent NSAID treatment

In another study in the June issue of Arthritis & Rheumatism,⁴ researchers found that ongoing NSAID treatment over a 2-year span decreases radiographic progression in patients with AS when compared with as-needed use of NSAIDs, without substantially increasing toxicity.

"While awaiting confirmation of these results, we carefully recommend that if patients need treatment with NSAIDs to reduce the signs and symptoms of AS, they should take them continuously instead of as-needed based on symptoms," Maxime Dougados, MD, professor of rheumatology at Groupe Hospitalier Cochin in Paris, France, comments in a press release.

In the study, patients were either prescribed twice-daily treatment with an NSAID, regardless of symptoms, or instructed to take an NSAID only when they had pronounced pain or stiffness. Both groups started treatment with celecoxib at a dosage of 100 mg and were allowed to increase their dosage to 200 mg if needed, or switch to another NSAID, as long as they maintained their assigned treatment strategy.

Overall, differences in spinal pain, night pain, morning stiffness, fatigue, and restricted mobility were not statistically significant between the two treatment groups, the study showed. No significant differences were reported in the gastrointestinal, respiratory, or cardiovascular health between groups. Although symptoms of depression occurred more frequently in the continuous-treatment group, there were no other differences in any other reported health problems. Only one case of severe abdominal pain requiring hospital admission - reported from the as-needed group - was deemed by the treating physician to be directly related to NSAID use.

There were, however, statistically significant differences in radiographic evidence of AS progression between the continuous-treatment and the as-needed groups, the study found. Twice as many patients in the as-needed group were scored as having moderate-to-high levels of spinal joint damage at the 2-year evaluation.

References:

1. Marzo-Ortega H, McGonagle D, Jarrett S, et al. Infliximab in combination with methotrexate in active ankylosing spondylitis. A clinical and imaging study. Ann Rheum Dis. 2005 May 26; [Epub ahead of print].
2. Davis JC, van der Heijde DM, Braun J, et al. Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks, Ann Rheum Dis. 2005 May 26; [Epub ahead of print].
3. Gossec L, van der Heijde D, Melian A, et al. Efficacy of cyclo-oxygenase-2 inhibition by etoricoxib and naproxen on the axial manifestations of ankylosing spondylitis in the presence of peripheral arthritis. Ann Rheum Dis. 2005 May 26; [Epub ahead of print].
4. Wanders A, van der Heijde D, Landewé R, et al. Nonsteroidal anti-inflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 2005;52:1756-1765.