Background The HONOR (humira discontinuation without functional and radiographic damage following sustained remission) study was designed to investigate the possibility of patients discontinuing adalimumab (ADA) therapy for 1 year without flaring (DAS28-ESR ≥3.2). 14–3-3η is a mechanistic serum marker that is modifiable over the disease course, does not correlate with CRP and is a predictor of radiographic progression even in patients who achieve clinical remission. The uncoupling of inflammation and joint damage processes in RA underscores a risk of premature discontinuation of biologic treatment when aiming to achieve sustained remission. Serum markers that could indicate which patients are at risk of flare and continued joint damage despite clinical remission are highly desirable.
Objectives In this study, serum 14–3-3η was investigated as a predictor of joint damage and flares in the HONOR cohort.
Methods Serum 14–3-3η levels were measured in 62 Japanese patients, 51 of which were from the HONOR study at baseline, 1-year after treatment initiation, at discontinuation and at the time of flare. Of the 62 patients, 46 (74%) patients achieved sustained drug-free remission up to 1 year following ADA discontinuation. Sharp van der Heidje (SHS) scores were available at therapy initiation, discontinuation, and at 52 weeks following. Relationships between continuous variables were assessed using uni- and multi-variable Gaussian linear regression models and logistic regression.
Results At baseline and discontinuation, median (QR) 14–3-3η levels were 0.28 ng/ml (0.07–2.11) and 0.22 ng/ml (0.04–1.28) respectively, with 26 (59%) of 44 and 29 (54%) of 54 patients being positive (≥0.19 ng/ml) at the corresponding time-points. Paired t-test revealed that levels of 14–3-3η were significantly different between baseline and discontinuation, p=0.030. Level of 14–3-3η at baseline was positively associated with SHS at 12 months and at the time of flare, p=0.038. Bivariable modeling revealed that baseline 14–3-3η together with the change in 14–3-3η had a significant interacting effect on SHS at 12 months and the time of flare, p=0.02. Higher baseline 14–3-3η levels together with an increase in levels at the time of discontinuation was strongly associated with an increased SHS. Adding CRP, flare, sustained remission through 12 months, MTX dose at initiation and at ADA discontinuation did not improve predictive effects of 14–3-3η with SHS. Baseline 14–3-3η levels alone was not associated with flares at 12 months (p=0.15) however when combined with CRP, a significant interaction was present (p=0.03). Specifically, patients with a low CRP, and a high 14–3-3η level had a higher likelihood of flaring versus those with a low 14–3-3η, 22% versus 12%.
Conclusions Baseline 14–3-3η and increases in its levels are associated with worse radiographic outcomes in patients who achieve clinical remission and discontinue ADA. To reduce the risk of flare in patients who are candidates for discontinuation of ADA, CRP and 14–3-3η measurements should be considered in combination as markers of flare prediction.
Disclosure of Interest S. Hirata: None declared, A. Marotta Employee of: Augurex Life Sciences Corp., K. Hanami: None declared, Y. Tanaka: None declared