Low Disease Activity Predicts Good Response in CAMEO Trial

Pam Harrison

March 17, 2014

Whistler, Canada — Patients with rheumatoid arthritis (RA) who achieve low disease activity or remission after 6 months on a combination of etanercept (ETN) plus methotrexate (MTX) continue to have clinically and radiographically stable disease out to 12 and even 24 months on ETN alone, updated analyses of the Canadian Methotrexate and Etanercept Outcome Study (CAMEO) show. The data were presented here February 28, 2014, at the 69th Annual Meeting of the Canadian Rheumatology Association.

Janet Pope, MD, professor of medicine, University of Western Ontario, London, Canada, and multicenter colleagues found that patients with moderate disease activity on study entry who achieved a state of low disease activity or remission after 6 months of the 2-drug approach had a mean Disease Activity Score 28 joint count (DAS28) score of 3.06 (95% confidence interval [CI], 2.59 - 3.52) at 12 months after discontinuation of MTX at month 6.

This compared with a mean DAS28 score of 3.10 (95% CI, 2.66 - 3.53) in the same subset of patients who remained on both drugs until month 12. The proportion of patients achieving a European League Against Rheumatism "good" or "moderate" response was similar in both treatment groups as well.

In contrast, patients with severe disease activity on study entry in whom MTX was discontinued at 6 months showed worsening disease at 12 months, with a mean DAS28 score of 4.31 (95% CI, 3.85 - 4.76).

This compared with a mean DAS28 score of 3.39 (95% CI 3.02 - 3.76) in patients with initially severe disease activity who remained on both study drugs out to month 12.

The proportion of patients with severe baseline disease activity who achieved a European League Against Rheumatism "good or "moderate" response at 12 months was also higher in the combination group.

"As physicians, we like MTX because we've had decades of experience with it, it can be given just once a week by pills or injection, and it's inexpensive," Dr. Pope told Medscape Medical News. However, in her experience, up to 30% of patients do not like MTX because they feel unwell when receiving it, not just for a short interval after taking the drug but for potentially days after, she added.

Some patients also develop "anticipatory" feelings of being unwell before taking their weekly MTX, so they are unwell most of the week. Rarely, Dr. Pope added, patients refuse MTX because they are not allowed to drink alcohol while receiving it and it is a lifestyle choice they do not wish to make.

"If a patient starts with high disease activity, it's still better to hold them on the 2 drugs and get ongoing improvement," Dr. Pope emphasized. "But if they are closer to low disease activity at the start, you are more likely to get patients down to a good disease state. So we're learning how to demedicate from this study."

CAMEO Cohort

CAMEO enrolled 258 patients with RA with a mean disease duration of 8.9 years. Patients were naive to tumor necrosis factor inhibitors on study entry but had been exposed to a mean of 2.7 prior disease-modifying antirheumatic drugs. Slightly more than half had received prior oral steroids as well. Patients had 3 or more swollen joints and a baseline DAS28 of 3.2 or greater despite stable MTX therapy.

ETN was given at a dose of 50 mg/week, subcutaneously, added to a background dose of MTX, either 15 mg/week or 10 mg/week if patients were intolerant to MTX at baseline. After 6 months of receiving both drugs, 205 patients were randomly assigned to either ETN alone (n=98) or to continue on ETN plus MTX (n=107). In this cohort, 84 patients had moderate baseline disease activity and 121 had severe baseline disease activity.

As Pope et al previously reported, withdrawing MTX after 6 months of receiving both drugs did not lead to the same degree of improvement between 6 and 12 months in the entire randomized cohort of 205 patients.

However, in prespecified, post hoc analyses presented here, investigators assessed disease improvement between 6 and 12 months according to baseline disease activity. Patients with low or moderate disease activity at baseline had a DAS28 score of lower than 3.2 and 5.1 or lower, whereas those with severe disease activity had a baseline DAS28 higher than 5.1.

At 6 months, 70% more patients with moderate baseline disease activity had achieved low disease activity or remission, defined as a DAS28 score lower than 3.2, the investigators report.

At 12 months, nearly twice as many patients with moderate disease activity, at 61.3%, had achieved low disease activity or remission compared with 35.8% of patients with severe baseline disease activity.

These findings suggest that MTX may be withdrawn in a relatively high proportion of patients with moderate disease activity at baseline after completing 6 months on the 2 drugs, the investigators conclude.

"This trial is important because in a Canadian context, this was the real world," Dr. Pope observed. "On average, our patients were on higher doses of MTX because we demanded that; they were on less oral steroids than they would be in a US or a European trial, and they had failed or been exposed to more disease-modifying drugs...than patients in a US or European trial. So we designed the trial to see if patients did better on 2 drugs rather than one, but there appears to be a subset of patients who don't need 2 drugs, which is good to know too."

24-Month Findings

In a related update of clinical and radiographic findings at 24 months, Boulos Haraoui, MD, associate professor of medicine, University of Montreal, Quebec, Canada, and multicenter colleagues again analyzed CAMEO findings at 24 months on the basis of disease activity at 6 months.

The mean baseline DAS28 score in the overall cohort was 5.4, whereas the mean baseline modified total Sharp score was 38.1.

From month 6 to month 24, mean clinical changes based on levels of disease activity and treatment group were as indicated in the table.

Table. Mean Change in DAS28 From Month 6

Time LDA at 6 Months: ETN Alone (N=45) LDA at 6 Months: ETN and MTX (N=47) MHDA at 6 Months: ETN Alone (N=50) MHDA at 6 Months: ETN and MTX (N=58)
To month 12 −0.66 −0.57 −0.36 0.39
To month 18 −0.85 −0.42 −0.33 0.44
To month 24 −0.91 −0.51 −0.23 0.27

LDA, low disease activity; MHDA, medium to high disease activity.

Investigators also reported that approximately 87% of patients with low disease activity or remission at 6 months had no significant radiographic progression at 24 months, regardless of the treatment received.

More patients in the combination group (76.4%) who still had moderate to high disease activity at 6 months also had no significant radiographic progression at the same endpoint. This compared with 63.8% of the same subset of patients taking ETN alone.

There was a trend toward a slightly better serious adverse event profile in the ETN monotherapy group, but the difference between the 2 groups was not significant.

"We know that a combination of medications is always better than a single drug, so we do not recommend people systematically stop MTX in these patients," Dr. Haraoui told Medscape Medical News.

"But if there is any valid reason to stop it, whether because of toxicity or tolerability issues, then we can be more reassured that we can stop MTX provided patients have achieved low disease activity or remission after 6 months of the combination therapy."

In contrast, he added, patients who still have moderate to high disease activity after 6 months of the 2-drug approach need to be encouraged to stay on MTX, as otherwise, "they will lose their response and flare again."

Commenting on the updated CAMEO trial findings, Claire Bombardier, MD, professor of medicine and director, Division of Rheumatology, University of Toronto, Ontario, Canada, told Medscape Medical News that the 12-month data are "convincing," in that they demonstrate that physicians can indeed withdraw MTX in patients with moderate disease activity at baseline, but not in patients with high baseline disease activity.

"This information is useful in clinical practice, as it allows physicians to discontinue MTX in a subset of patients with moderate disease activity who do not tolerate MTX or who are not comfortable taking frequent pills or injections." On the basis of radiographic outcomes at 24 months that favor the combination compared with etanercept alone, Dr. Bombardier still cautioned that clinicians should try to maintain patients on both drugs if possible.

In contrast, she emphasized that patients randomly assigned to CAMEO had long-standing disease and had received multiple prior disease-modifying antirheumatic drugs before study entry.

"There results therefore may not apply to patients with new onset of disease or to the majority of RA patients, [who] are in low to moderate disease activity."

This study was funded by Amgen. Both Dr. Pope and Dr. Haraoui have received grants from multiple pharmaceutical companies including Amgen.

69th Annual Meeting of the Canadian Rheumatology Association: Abstracts 122 and 123. Presented February 28, 2014.

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