Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial.

BACKGROUND: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. METHODS: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). FINDINGS: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. INTERPRETATION: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. FUNDING: Innovative Medicine Initiative.

A predictive model for progression to clinical arthritis in at-risk individuals with arthralgia based on lymphocyte subsets and ACPA.

BACKGROUND: The presence of autoantibodies against citrullinated proteins (ACPA) significantly increases the risk of developing rheumatoid arthritis (RA). Dysregulation of lymphocyte subpopulations was previously described in RA. OBJECTIVES: To propose the predictive model for progression to clinical arthritis based on peripheral lymphocyte subsets and ACPA in individuals who are at risk of RA. METHODS: Our study included 207 at-risk individuals defined by the presence of arthralgias and either additional ACPA positivity or meeting the EULAR definition for clinically suspect arthralgia. For the construction of predictive models, 153 individuals with symptom duration ≥12 months who have not yet progressed to arthritis were included. The lymphocyte subsets were evaluated using flow cytometry and anti-CCP using ELISA. RESULTS: Out of all individuals with arthralgia, 41 progressed to arthritis. A logistic regression model with baseline peripheral blood lymphocyte subpopulations and ACPA as predictors was constructed. The resulting predictive model showed that high anti-CCP IgG, higher percentage of CD4+ T cells, and lower percentage of T and NK cells increased the probability of arthritis development. Moreover, the proposed classification decision tree showed, that individuals having both high anti-CCP IgG and low NK cells have the highest risk of developing arthritis. CONCLUSIONS: We propose a predictive model based on baseline levels of lymphocyte subpopulations and ACPA to identify individuals with arthralgia with the highest risk of progression to clinical arthritis. The final model includes T cells and NK cells, which are involved in the pathogenesis of RA. This preliminary model requires further validation in larger at-risk cohorts.

Integrative non-pharmacological care for individuals at risk of rheumatoid arthritis.

There is increasing knowledge in the recognition of individuals at risk for progression to rheumatoid arthritis (RA) before the clinical manifestation of the disease. This prodromal phase preceding the manifestation of RA may represent a "window of opportunity" for preventive interventions that may transform the clinical approach to this disease. However, limited evidence exists in support of effective interventions to delay the onset or even halt the manifestation of RA. Given the multifactorial nature of RA development and disease progression, the latest guidelines for established RA stress the use of integrative interventions and multidisciplinary care strategies, combining pharmacologic treatment with non-pharmacological approaches. Accordingly, individuals at risk of RA could be offered an integrative, multifactorial intervention approach. Current data point toward pharmacological intervention reverting the subclinical inflammation and delay in the disease onset. In addition, targeting life style modifiable factors (smoking cessation, dental health, physical activity, and diet) may presumably improve RA prognosis in individuals at risk, mainly by changes in epigenetics, autoantibodies, cytokines profiles, and microbiome. Nonetheless, the benefits of multidisciplinary interventions to halt the manifestation of RA in at-risk individuals remain unknown. As there is a growing knowledge of possible pharmacological intervention in the preclinical phase, this narrative review aims to provide a comprehensive overview of non-pharmacological treatments in individuals at risk of RA. Considering the mechanisms preceding the clinical manifestation of RA we explored all aspects that would be worth modifying and that would represent an integrative non-pharmacological care for individuals at risk of RA.