The presence of low disease activity (LDA) with a lower incidence of adverse effects was reported in approximately 80% of patients who discontinued Adalimumab (ADA) for 3 years after achieving LDA with ADA + Methotrexate (MTX), as compared to patients who continued ADA.

Rheumatoid arthritis (RA) is a progressive inflammatory disease causing joint destruction, thus functional disability. Various biological agents such as tumor necrosis factor inhibitors (TNFi) have significantly increased clinical remission rates in RA. Recent research have shown that a biological therapy in combination with MTX is highly efficacious than MTX monotherapy. However, continuous use of biological therapies can lead to serious adverse effects imposing an economic burden on patients. Researchers have evaluated the usefulness of discontinuing the biological agents in patients who have already achieved LDA. Two studies, the OPTIMA trial and HONOR study recommended that the achievement of disease control with initial intensive therapy may help in the prevention of disease flare after discontinuation of ADA. These findings are clinically important; however, the effects of ADA discontinuation over a longer period (i.e., >1 year) remain unknown. Therefore, this HOPEFUL-3 study, a follow-up to the HOPEFUL-1 and HOPEFUL-2 studies were conducted. The study HOPEFUL-1 evaluated the effects of ADA +MTX and MTX alone for 26 weeks, whereas HOPEFUL-2 evaluated the effects of ADA discontinuation on RA disease activity over a period of 52 weeks. The present, HOPEFUL-3 study involved patients who have completed HOPEFUL-2 to assess the long-term effects of ADA discontinuation on the percentage of patients without disease flare, and other measures of RA activity and safety.

Rationale behind the research:

• There is a lack of data suggesting the long-term effects associated with discontinuation of biological therapies like ADA in treatment of RA
• This study notifies the long-term effects associated with discontinuation of ADA after achieving low disease activity in patients with RA

Objective:

To evaluate the feasibility of discontinuation of long-term ADA after achievement of low LDA in early rheumatoid arthritis (RA) patients and to identify predictors of LDA maintenance.

Study outcome measures

Baseline: Patients characteristics such as age, female sex, duration of treatment, prior MTX dose and steroid use in ADA continuation & discontinuation group was measured at baseline.

• Primary endpoints: Changes in DAS28-CRP and the proportion of patients who achieved LDA (DAS28-CRP < 3.2) at week 208 were the primary endpoints.
• Secondary endpoints: The proportion of patients who achieved clinical remission (DAS28-CRP <2.6), and changes in Health Assessment Questionnaire Disability Index (HAQ-DI) and modified total Sharp score (mTSS) at week 208 were the secondary endpoints.
• Safety measures: Adverse effects associated with discontinuation of ADA were also recorded at week 208.

Time Points: Baseline and at week 52, 104 and 208

Study outcomes Baseline: There were no significant differences observed in baseline characteristics Primary outcomes: At week 208, 58 (95.1%) of 61 patients and 59 (79.7%) of 74 patients who continued or discontinued ADA, respectively, had LDA (DAS28-CRP <3.2) {Fig1 (a,b,c)}. Secondary outcomes: Initial intensive therapy was associated with a better outcome than standard therapy regarding change in modified total Sharp score from week 0 to week 208, which was ≤0.5 (64% vs. 30%) {Fig 2}. Safety outcomes: The incidence of adverse events was significantly lower in the ADA discontinuation group than in the ADA continuation group (9.7% vs. 32.9%; p<0.001)

Fig 1(a): Comparison of proportion of patients with LDA at the end of the HOPEFUL-3 study period (week-208)

Fig 1(b) Patients with LDA in ADA continuation group

Fig 1(c) Patients with LDA in ADA discontinuation group

In this HOPEFUL-3 study, LDA after discontinuation of ADA was investigated, and the results predicted that patients were in LDA after 2 years of ADA discontinuation. The patients who achieved LDA at week 208 were lower in ADA discontinuation group as compared to ADA continuation group. There is a great value of early prediction of long-term clinical outcomes for physicians during the treatment course. In HOPEFUL-2 study, DAS28-CRP was identified as a factor associated with persistence of LDA, but in this study, its value was lower than identified in HOPEFUL-2 study.

Biological agents result in clinical, functional, and structural remission but are often linked with various serious adverse effects. No cases of tuberculosis and deaths were reported in this study. Patients who continued to take ADA were more prone to adverse event than those who discontinued ADA. It was found that discontinuation of biological agents after achieving LDA may reduce the economic burden associated with long-term use of biological agents, but there is a need of further research to clarify cost-benefit perspective with long-term use of biological agents. At last, it is inferred that the results of this study are not conclusive, but they suggest the feasibility and benefits of long-term discontinuation of ADA treatment for patients with early RA who achieved LDA.