RA Activity Stable After Prolonging Adalimumab Interval

Diana Swift

September 27, 2017

Patients with rheumatoid arthritis (RA) can safely extend interdose intervals of adalimumab by 50% without adversely affecting disease activity, a noninferiority trial has found.

Merel J. l'Ami, MSc, from the Amsterdam Rheumatology and Immunology Center at Reade, Amsterdam, the Netherlands, and colleagues report their findings in an article published online September 22 in the Annals of the Rheumatic Diseases.

The researchers found that patients with serum trough adalimumab concentrations of more than 8 μg/mL were able to lengthen dosing intervals from the standard of once every 2 weeks to once every 3 weeks with no diminution of disease control.

At the end of 28 weeks, the mean difference in the primary outcome measure of the Disease Activity Score in 28 joints (DAS28) was −0.14 ± standard deviation 0.61 in the prolongation group (n = 27), a slight improvement, compared with 0.30 ± standard deviation 0.52 in the continuation group (n = 24), a slight deterioration. The mean difference significantly favored the prolongation group: 0.44 (95% confidence interval, −0.76 to −0.12, P = .01), indicating noninferiority of the experimental protocol.

Although higher concentrations of the anti-TNF biologic can improve clinical response, the curve typically plateaus at a cutoff point of approximately 5 μg/mL, the concentration considered necessary to block the inflammatory effects of TNF, and many patients in remission may remain so at even lower levels, the authors note. Those with steady-state trough concentrations above 5 μg/mL are probably overexposed and at higher risk for infections. "Identification of and acting on overexposure will reduce drug costs and possibly risk of adverse events," the authors write.

The open-label, parallel-group, noninferiority study screened 147 consecutive patients receiving adalimumab 40 mg every other week for at least 28 weeks. Of those screened, 55 had enzyme-linked immunosorbent assay-measured trough concentrations higher than 8 μg/mL. The researchers randomly assigned those participants in a 1:1 ratio to either dose-interval prolongation with injection once every 3 weeks or continuation of the standard schedule of every other week.

Mean ages were similar at 60 years in the prolongation group and 58 in the continuation group, and median disease duration in both groups was 11 years.

The primary outcome was change in the DAS28-erythrocyte sedimentation rate after 28 weeks, with a noninferiority margin of 0.6 points considered clinically relevant. Other endpoints were changes in the Clinical Disease Activity Index and Simplified Disease Activity Index, as well as serum adalimumab concentrations.

Seven patients (26%) in the prolongation group compared with 10 patients (37%) in the continuation group showed an increase in DAS28 of at least 0.6 points after 28 weeks (P = .56). Two of the seven prolongation patients with worsened DAS28 opted to return to standard dosing, and four others on prolongation also preferred to return to the standard schedule.

Results were similar in both groups for the Clinical Disease Activity Index and Simplified Disease Activity Index.

At 28 weeks, mean adalimumab concentration in the 26 evaluable prolonged interval patients decreased from 10.6 ± 2.5 μg/mL to 6.6 ± 2.0 μg/mL, with seven patients having concentrations fall below 5 μg/mL. One of the seven had an increase in DAS28 of at least 0.6 and returned to standard dosing. In the 23 continuation patients, adalimumab concentration fell slightly from 10.4 ± 2.4 μg/mL to 9.3 ± 3.0 μg/mL, for a mean intergroup difference of 2.6 μg/mL (95% confidence interval, 1.2 - 4.1 μg/mL; P = .001).

No serious adverse events occurred, and two patients in the prolongation group reported an adverse event compared with 14 in the continuation group.

In the Netherlands, lengthening the dosing interval for anti-TNF treatment could reduce annual drug costs by 33% per year, on the basis of a yearly per patient cost of &eur;5000 (nearly $6000 USD), the authors write.

Other recent research has shown that tapering the dosing interval reduces drug levels, but not disease control. And a French study covered by Medscape Medical News found that many patients with rheumatoid arthritis could safely taper their biologics with no increase in disease activity or functional impairment.

"Beyond the scope of our study, similar concentration-response relationships have been published for adalimumab treatment in psoriatic arthritis and psoriasis, suggesting overexposure may be a feature in these diseases as well. Moreover, this study demonstrates the potential benefit of therapeutic drug monitoring," the authors explain.

The study was partly funded by the Dutch Arthritis Foundation. All study authors except for lead author l'Ami report relationships with industry partners, including Pfizer, AbbVie, Merck, Roche, Bristol-Myers Squibb, Union Chinique Belge, Eli Lilly, Celgene, Amgen, BMS, GlaxoSmithKline, Biotest, Crescendo, Janssen, Novartis, Vertex, Regeneron, Genmab, Teva, and Biogen.

Ann Rheum Dis. Published online September 22, 2017. Abstract

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