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.

JAK/STAT signaling in rheumatoid arthritis leukocytes is uncoupled from serum cytokines in a subset of patients.

OBJECTIVE: Rheumatoid Arthritis (RA) is a systemic autoimmune disease involving pro-inflammatory cytokines that can be therapeutically targeted by antibodies or kinase inhibitors. Nevertheless, these drugs fail in a subset of patients independent of the abundance of the targeted cytokines. We aim to explore the cellular basis of this phenomenon by analyzing the relation of cytokine abundance and activation of downstream signaling pathways in RA. METHODS: The study included 62 RA patients and 9 healthy controls (HC). Phosphorylation of STAT 1-6 in various immune cell subsets was determined ex vivo using a novel robust flow cytometry-based protocol. Serum concentrations of IL-6, IL-10, IL-12p70, IL-17 A, interferon gamma, and TNFα in the same samples were measured using highly sensitive single molecule array (SIMOA). RESULTS: We found an increase in circulating cytokines in RA patients, while STAT activity was lower in RA patients compared to HC. Based on STAT activity we determined three endotypes in active RA patients (cDAI>10, n = 28): 1) those with active STAT5a/b signaling in T cells (n = 7/28), 2) those with a low STAT activity in all assessed cell types (n = 14/28), and 3) those with active STAT1 and STAT3 signaling mainly in myeloid cells (n = 7/28). Integrating intracellular STAT activation and cytokine analysis revealed diminished JAK/STAT signaling in a subset of patients (n = 8/20) despite elevated serum cytokine concentrations. CONCLUSION: Diminished JAK/STAT signaling in active RA may partly explain unresponsiveness to therapy targeting cytokine signaling. Analysis of JAK/STAT phosphorylation may identify patients at risk for non-response to these therapies.

Defects in B-lymphopoiesis and B-cell maturation underlie prolonged B-cell depletion in ANCA-associated vasculitis.

OBJECTIVES: B-cell depletion time after rituximab (RTX) treatment is prolonged in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with other autoimmune diseases. We investigated central and peripheral B-cell development to identify the causes for the defect in B-cell reconstitution after RTX therapy. METHODS: We recruited 91 patients with AAV and performed deep phenotyping of the peripheral and bone marrow B-cell compartment by spectral flow and mass cytometry. B-cell development was studied by in vitro modelling and the role of BAFF receptor by quantitative PCR, western blot analysis and in vitro assays. RESULTS: Treatment-naïve patients with AAV showed low transitional B-cell numbers, suggesting impaired B-lymphopoiesis. We analysed bone marrow of treatment-naïve and RTX-treated patients with AAV and found reduced B-lymphoid precursors. In vitro modelling of B-lymphopoiesis from AAV haematopoietic stem cells showed intact, but slower and reduced immature B-cell development. In a subgroup of patients, after RTX treatment, the presence of transitional B cells did not translate in replenishment of naïve B cells, suggesting an impairment in peripheral B-cell maturation. We found low BAFF-receptor expression on B cells of RTX-treated patients with AAV, resulting in reduced survival in response to BAFF in vitro. CONCLUSIONS: Prolonged depletion of B cells in patients with AAV after RTX therapy indicates a B-cell defect that is unmasked by RTX treatment. Our data indicate that impaired bone marrow B-lymphopoiesis results in a delayed recovery of peripheral B cells that may be further aggravated by a survival defect of B cells. Our findings contribute to the understanding of AAV pathogenesis and may have clinical implications regarding RTX retreatment schedules and immunomonitoring after RTX therapy.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 266 AAV patients.

OBJECTIVES: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry. METHODS: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. RESULTS: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry: 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%). CONCLUSIONS: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 195 GCA patients.

OBJECTIVES: Giant cell arteritis (GCA) is one of the most common forms of vasculitis. There is an abundance of studies which are conducted in a randomised controlled trial setting but limited with respect to cohort size and follow-up time. GeVas is the first large-scale registry for vasculitides in German-speaking countries that enables to evaluate this rare disease. Herein we focus on the subgroup of GCA patients including follow-up data up to one year. METHODS: GeVas is a prospective, web-based, multicentre registry for the documentation of organ manifestations, outcomes, and therapy regimens in vasculitides. Recruitment started in June 2019. By April 2023, 15 centres were initiated and have started to enrol patients. RESULTS: After 4 years, 195 GCA-patients were included in the registry, of which 64% were female and 36% were male. The average age was 76 years at the time of recruitment (IQR=69-82). Seventy-nine percent were included in the registry because of a newly diagnosed GCA and 21% because of a relapse. At the first assessment most of the patients (89%) described general symptoms. Thirty-one percent stated ocular symptoms. Cranial symptoms were documented in 78% of the cases. All patients were documented with immunosuppressive treatment at start, of whom 95% received prednisolone, 16% cyclophosphamide, 20% methotrexate, and 48% tocilizumab. After three months 62% and after one year 91% of the patients achieved remission. CONCLUSIONS: Regarding demographics, clinical manifestations and diagnostics, our study showed a similar composition compared to other studies. However, our data differed in terms of treatment regimens.

Genetic relationship between rheumatoid arthritis and cardiovascular diseases : A systematic review of Mendelian randomization studies.

OBJECTIVE: Rheumatoid arthritis (RA) is recognized as a chronic autoimmune disorder with systemic inflammation and joint damage. Its potential role as a risk factor for cardiovascular diseases (CVD) is increasingly noted. This review delves into the causal relationship between RA and CVD, with Mendelian randomization (MR) offering a genetic perspective. METHODS: An extensive search was conducted in PubMed, Cochrane and Web of Science to identify MR studies addressing the RA-CVD link. Out of 530 studies, 9 met the inclusion criteria, which were rigorously assessed using a critical appraisal checklist. These were further stratified by a sensitivity analysis into categories reflecting the strength of their evidence, from not evaluable to robust. RESULTS: From the nine included studies, eight supported a causal association between RA and an increased risk of CVD, specifically coronary artery disease (CAD) and one did not support a link between RA and heart failure. The results suggest that genetic factors associated with RA may contribute to an elevated risk for CVD. Chronic inflammation, prevalent in RA, emerges as a key mediator in this connection. CONCLUSION: The systematic review corroborates a genetic causal link between RA and CVD, as evidenced by eight of the nine MR studies reviewed. This suggests a need for integrated cardiovascular risk management in the treatment of RA patients. The findings advocate considering anti-inflammatory treatment that can reduce cardiovascular risk. The overarching evidence signifies a potential direction for new therapeutic strategies aimed at enhancing cardiovascular health in RA patients.

Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells.

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.

The IL-17 pathway as a target in giant cell arteritis.

The network of IL-17 cytokines is considered a key component of autoimmune and inflammatory processes. Blocking IL-17 showed great success in psoriasis as well as psoriatic arthritis, and in patients with axial spondyloarthritis. Secukinumab is one of the approved IL-17A inhibitors for these diseases and is now routinely used. In giant cell arteritis, a large vessel vasculitis, there is accumulating evidence for a pathogenic role of IL-17 and Th17 cells, which are part of the CD4+ T-cell subset. Giant cell arteritis occurs in individuals over 50 years of age and many have relative contraindications to glucocorticoid therapy, which today still represents the mainstay therapy. Despite the approval of tocilizumab, which targets the IL-6 receptor, a high demand for glucocorticoid-sparing agents remains that combine the effective suppression of the acute inflammation observed in giant cell arteritis with a safety profile that matches the needs of an older patient population. The first results from a phase II proof-of-principle study (TitAIN) support an optimistic outlook on a potential new treatment option with secukinumab in giant cell arteritis.

Safety and efficacy of secukinumab in patients with giant cell arteritis (TitAIN): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis. METHODS: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion. Participants were assigned (1:1) to receive 300 mg secukinumab or placebo subcutaneously once a week up to week 4 and every 4 weeks thereafter. In both treatment groups, prednisolone dose was tapered down to 0 mg over a 26-week period. Patients, investigator staff, and clinical trial team were masked to the treatment assignment. The primary endpoint was the median proportion (Bayesian analysis) of patients with sustained remission until week 28 in the full analysis set (ie, all patients who received at least one dose of assigned treatment, analysed according to treatment assigned at randomisation). Sustained remission rate of the placebo group from a previous trial of tocilizumab in patients with giant cell arteritis was used to derive the prior distribution of placebo sustained remission rate for the primary endpoint. The safety of secukinumab was assessed in the safety set (ie, all patients who received at least one dose of study treatment, analysed according to study treatment received). This trial is completed and is registered with ClinicalTrials.gov, NCT03765788. FINDINGS: Of the 65 patients who were assessed for eligibility, 52 patients (median age 75 years [IQR 69-79]; 35 [67%] female and 17 [33%] male, 52 [100%] White) were enrolled between Jan 30, 2019 and March 30, 2020 and were randomly assigned to receive secukinumab (n=27) or placebo (n=25). Four of 27 patients in the secukinumab group and eight of 25 patients in the placebo group discontinued treatment by week 28 of the study. On the basis of the Bayesian analysis, the median proportion of patients in sustained remission until week 28 was 70% (95% credibility interval 52-85) in the secukinumab group versus 20% (12-30) in the placebo group. The incidence of adverse events was similar in the secukinumab (27 [100%] of 27 patients had any adverse event) and placebo groups (24 [96%] of 25 patients had any adverse event); the most common adverse events were hypertension (six [22%] of 27 patients in the secukinumab group and eight [32%] of 25 patients in the placebo group) and nasopharyngitis (five [19%] of 27 patients in the secukinumab group and five [20%] of 25 patients in the placebo group). Two patients (one in each group) died during the study, neither of which was considered to be related to study treatment. INTERPRETATION: Patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, in combination with glucocorticoid taper regimen. Secukinumab was tolerated well with no new safety concerns. This proof-of-concept phase 2 study further supports the development of secukinumab as a treatment option for people with giant cell arteritis. FUNDING: Novartis Pharma.