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.

2023 EULAR recommendations on imaging in diagnosis and management of crystal-induced arthropathies in clinical practice.

OBJECTIVE: To formulate evidence-based recommendations and overarching principles on the use of imaging in the clinical management of crystal-induced arthropathies (CiAs). METHODS: An international task force of 25 rheumatologists, radiologists, methodologists, healthcare professionals and patient research partners from 11 countries was formed according to the EULAR standard operating procedures. Fourteen key questions on the role of imaging in the most common forms of CiA were generated. The CiA assessed included gout, calcium pyrophosphate deposition disease and basic calcium phosphate deposition disease. Imaging modalities included conventional radiography, ultrasound, CT and MRI. Experts applied research evidence obtained from four systematic literature reviews using MEDLINE, EMBASE and CENTRAL. Task force members provided level of agreement (LoA) anonymously by using a Numerical Rating Scale from 0 to 10. RESULTS: Five overarching principles and 10 recommendations were developed encompassing the role of imaging in various aspects of patient management: making a diagnosis of CiA, monitoring inflammation and damage, predicting outcome, response to treatment, guided interventions and patient education. Overall, the LoA for the recommendations was high (8.46-9.92). CONCLUSIONS: These are the first recommendations that encompass the major forms of CiA and guide the use of common imaging modalities in this disease group in clinical practice.

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry.

OBJECTIVE: Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). METHODS: From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. RESULTS: At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. CONCLUSION: Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.

Long-term effect of tocilizumab in patients with giant cell arteritis: open-label extension phase of the Giant Cell Arteritis Actemra (GiACTA) trial.

BACKGROUND: The combination of tocilizumab plus a glucocorticoid taper is effective in maintaining clinical remission without requiring additional glucocorticoid therapy in patients with giant cell arteritis, as shown in part one of the Giant Cell Arteritis Actemra (GiACTA) trial. However, the duration of the tocilizumab effect after discontinuation is unknown. Here, we explored the maintenance of efficacy 1 year after discontinuation of tocilizumab treatment, the effectiveness of retreatment with tocilizumab after relapse, and the long-term glucocorticoid-sparing effect of tocilizumab. METHODS: In part one of the GiACTA trial, 251 patients were randomly assigned (2:1:1:1) to receive subcutaneous tocilizumab (162 mg) once a week or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Patients in clinical remission stopped masked injections at 1 year (the conclusion of part one). In part two, treatment was at the investigators' discretion and could consist of no treatment, tocilizumab, glucocorticoids, methotrexate, or combinations of these, for two years. Maintenance of efficacy as assessed by clinical remission (defined as absence of relapse determined by the investigator), cumulative glucocorticoid dose, and long-term safety were exploratory objectives in part two of the trial. This trial is registered at ClinicalTrials.gov, NCT01791153. FINDINGS: 215 patients participated in part two of the trial; 81 patients who were randomly assigned to tocilizumab once a week in part one were in clinical remission after 1 year, of whom 59 started part two on no treatment. 25 of these 59 patients (42%) maintained tocilizumab-free and glucocorticoid-free clinical remission throughout part two. Median (95% CI) cumulative glucocorticoid doses over 3 years were 2647 mg (1987-3507) for tocilizumab once a week, 3948 mg (2352-5186) for tocilizumab-every-other-week, 5277 mg (3944-6685) for placebo with a 26-week prednisone taper, and 5323 mg (3900-6951) for placebo with a 52-week prednisone taper (van Elteren p≤0·001, tocilizumab once a week vs placebo groups; p<0·05, tocilizumab-every-other-week vs placebo groups). Tocilizumab-based regimens restored clinical remission among patients who experienced relapse in part two and were treated (median time to remission: 15 days for tocilizumab alone [n=17]; 16 days for tocilizumab plus glucocorticoids [n=36]; and 54 days for glucocorticoids alone [n=27]). No new or unexpected safety findings were reported over the full 3 years of the study. INTERPRETATION: Giant cell arteritis remains a chronic disease that entails ongoing management and careful vigilance for disease relapse, but continuous indefinite treatment with immunosuppressive drugs is not required for all patients. A substantial proportion of patients treated with tocilizumab for one year maintain drug-free remission during the two years after tocilizumab cessation. For patients who experience relapse, tocilizumab can be used to manage relapses, but it remains prudent to include prednisone for patients who experience relapse because of the risk for vision loss. FUNDING: F Hoffmann-La Roche.

Treatment tapering and stopping in patients with rheumatoid arthritis in stable remission (RETRO): a multicentre, randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms. METHODS: RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel-group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score <2·6 units). Eligible patients were recruited consecutively from 14 German hospitals or rheumatology practices and randomly assigned (1:1:1) without stratification and regardless of baseline treatment, using a sequence that was computer-generated by the study statistician, to continue 100% dose DMARD (continue group), taper to 50% dose DMARD (taper group), or 50% dose DMARD for 6 months before stopping DMARDs (stop group). Neither patients nor investigators were masked to the treatment assignment. Patients were assessed every 3 months and screened for disease activity and relapse. The primary endpoint was the proportion of patients in sustained DAS28-ESR remission without relapse at 12 months, analysed using a log-rank test of trend and Cox regression. Analysis by a trained statistician of the primary outcome and safety was done in a modified intention-to-treat population that included participants with non-missing baseline data. This study is completed and closed to new participants and is registered with ClinicalTrials.gov (NCT02779114). FINDINGS: Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3-90·0) in the continue group, 58·6% (49·2-70·0) in the taper group, and 43·3% (34·6-55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69-5·40; p=0.0003) for the taper group and 4·34 (2·48-7·60; p<0.0001)) for the stop group, in comparison with the continue group. The majority of patients who relapsed regained remission after reintroduction of 100% dose DMARDs. Serious adverse events occurred in ten of 93 (11%) patients in the continue group, seven of 93 (8%) patients in taper group, and 13 of 96 (14%) patients in the stop group. None were considered to be related to the intervention. The most frequent type of serious adverse event was injuries or procedural complications (n=9). INTERPRETATION: Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis. FUNDING: None.