medwireNews: Stopping adalimumab in children with controlled juvenile idiopathic arthritis (JIA)-associated uveitis commonly leads to a return of inflammation, show the results of the ADJUST double-blind, randomized controlled trial.
Treatment failure, defined as the recurrence of uveitis or arthritis, at the prespecified interim analysis occurred in 68% of 44 children who had controlled JIA-associated uveitis for at least a year and stopped adalimumab to receive placebo instead and in 14% of 43 similar children who continued adalimumab treatment. The hazard ratio of 8.7 was significantly in favor of continued adalimumab treatment and the trial was stopped because more than 40% of the anticipated treatment failures had occurred.
“The high rate of relapse after stopping adalimumab calls into question current recommendations regarding the timing for attempting withdrawal,” write Nisha Acharya (University of California at San Francisco, USA) and fellow members of the ADJUST study group in The Lancet.
According to the American College of Rheumatology and NHS England, adalimumab withdrawal should only be considered after a prolonged period of disease stability, of at least 2 years and 18 months, respectively. These recommendations are based on limited evidence, however, say the researchers.
ADJUST was conducted at 20 ophthalmology and rheumatology centers in the USA, UK, and Australia. Recruitment started in March 2020 and ended in February 2024.
Of the 87 children included in the study, 74% were female, 77% were white, and the median age was 12.3 years in the placebo group and 12.6 years in the adalimumab group. The main reason for treatment with adalimumab was uveitis on its own in about two thirds of cases, with about one third of cases involving both uveitis and arthritis. The majority (71%) of participants had more than 2 years of controlled uveitis.
Adalimumab or matched placebo were given subcutaneously every 2 weeks until treatment failure or until the final study visit, which was planned to be at 48 weeks. Adalimumab was dosed according to bodyweight, with those continuing adalimumab given 20 mg if they weighed less than 30 kg or 40 mg if they weighed 30 kg or more.
“Most treatment failures were due to recurrence of uveitis and occurred in the first 24 weeks after stopping treatment,” say the researchers. They report that the median time to treatment failure was 119 days in the placebo group.
“If an attempt is made to withdraw therapy, patients should be closely monitored for recurrence, especially during the first 6 months,” Acharya et al suggest. But, if treatment is restarted, “[p]atients can be reassured that disease control can be regained.”
The median time to achieving sustained control of ocular inflammation after treatment failure was 105 days in the placebo group and 98 days in the adalimumab group. And the investigators note that visual acuity was unaffected by adalimumab discontinuation.
While not statistically significant, there was an indication that younger children were at higher risk for treatment failure than those aged 12 years or older. There was also a nonsignificant increase in treatment failure associated with a longer (>2 years) duration of uveitis control with adalimumab prior to its discontinuation.
“The adverse events seen in this study were as expected for adalimumab treatment, with higher rates of infection, such as COVID-19, in the adalimumab group probably a result of increased immunosuppression,” the ADJUST study group writes.
Overall, however, the adverse event rate was similar for the two treatment groups, at 7.5 per person–year among patients who discontinued adalimumab and 6.8 per person–year among those who did not. The most common adverse events were gastrointestinal (51 vs 19 events, respectively), headache (24 vs 20 events), and fatigue (28 vs 12 events).
There were four serious adverse events – surgery for torted cyst of Morgagni, shortness of breath at rest, planned orthognathic surgery, and increased alanine aminotransferase levels – all of which occurred among patients who continued adalimumab treatment, with the increased alanine aminotransferase levels considered possibly related to the drug.
“Results from this clinical trial can be used to guide counselling of patients and families who are considering discontinuing adalimumab for juvenile idiopathic arthritis-associated uveitis,” the ADJUST study group believes.
Dirk Foell (University Hospital Muenster, Germany) and Arnd Heiligenhaus (St Franziskus Hospital, Muenster, Germany) jointly congratulate the ADJUST study group in a related comment.
“A prospective, randomised study on the effects of continuing or discontinuing adalimumab in patients with controlled juvenile idiopathic arthritis-associated uveitis was urgently needed,” Foell and Heiligenhaus say.
They note: “The main limitation of the ADJUST trial is that in this analysis of primary outcome results no clinical or molecular predictive markers could be identified that would allow a prediction of the outcome for patients.”
Nevertheless, the commentators conclude that “the ADJUST results have substantial implications for the practical management of juvenile idiopathic arthritis-associated uveitis.”
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