Biological impact of iberdomide in patients with active systemic lupus erythematosus.

OBJECTIVES: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). METHODS: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling. RESULTS: Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (-58.3%), and plasmacytoid dendritic cells (-73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (-81.5%; p<0.001) but decreased other gene signatures in all patients. CONCLUSION: Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature. TRIAL REGISTRATION NUMBER: NCT03161483.

Treat to target in systemic lupus erythematosus / Tratamiento por objetivos en el lupus eritematoso sistémico

ABSTRACT Systemic lupus erythematosus (SLE) is the most representative disorder within systemic autoimmune diseases. The treat-to-target strategy in SLE was established half a decade ago and, since then, remarkable advances have been made. An international consensus has defined and unified the term remission and also low disease activity has been proposed as an alternative and, perhaps, more realistic target. Both of them have proven to be meaningful in terms of improving several outcomes, and have opened the path for future research in clinical trials.

RESUMEN El lupus eritematoso sistémico (LES) es el trastorno más representativo dentro de las enfermedades autoinmunes sistémicas. La estrategia de tratamiento por objetivos en el LES se estableció hace media década y desde entonces se han producido notables avances. Un consenso internacional ha definido y unificado el término remisión y también se ha propuesto la baja actividad de la enfermedad como un objetivo alternativo y quizás más realista. Ambos han demostrado ser significativos en cuanto a la mejora de varios resultados y han abierto el camino para futuras investigaciones en ensayos clínicos.

Anti-beta 2 glycoprotein I IgA in the SLICC classification criteria dataset.

OBJECTIVE: Anti-beta 2 glycoprotein I IgA is a common isotype of anti-beta 2 glycoprotein I in SLE. Anti-beta 2 glycoprotein I was not included in the American College of Rheumatology (ACR) SLE classification criteria, but was included in the Systemic Lupus International Collaborating Clinics (SLICC) criteria. We aimed to evaluate the prevalence of anti-beta 2-glycoprotein I IgA in SLE versus other rheumatic diseases. In addition, we examined the association between anti-beta 2 glycoprotein I IgA and disease manifestations in SLE. METHODS: The dataset consisted of 1384 patients, 657 with a consensus physician diagnosis of SLE and 727 controls with other rheumatic diseases. Anti-beta 2 glycoprotein I isotypes were measured by ELISA. Patients with a consensus diagnosis of SLE were compared to controls with respect to presence of anti-beta 2 glycoprotein I. Among patients with SLE, we assessed the association between anti-beta 2 glycoprotein I IgA and clinical manifestations. RESULTS: The prevalence of anti-beta 2 glycoprotein I IgA was 14% in SLE patients and 7% in rheumatic disease controls (odds ratio, OR 2.3, 95% CI: 1.6, 3.3). It was more common in SLE patients who were younger patients and of African descent (p = 0.019). Eleven percent of SLE patients had anti-beta 2 glycoprotein I IgA alone (no anti-beta 2 glycoprotein I IgG or IgM). There was a significant association between anti-beta 2 glycoprotein I IgA and anti-dsDNA (p = 0.001) and the other antiphospholipid antibodies (p = 0.0004). There was no significant correlation of anti-beta 2 glycoprotein I IgA with any of the other ACR or SLICC clinical criteria for SLE. Those with anti-beta 2 glycoprotein I IgA tended to have a history of thrombosis (12% vs 6%, p = 0.071), but the difference was not statistically significant. CONCLUSION: We found the anti-beta 2 glycoprotein I IgA isotype to be more common in patients with SLE and in particular, with African descent. It could occur alone without other isotypes.

A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self-Administered Questionnaires.

Nonadherence to treatment is a major cause of lupus flares. Hydroxychloroquine (HCQ), a major medication in systemic lupus erythematosus, has a long half-life and can be quantified by high-performance liquid chromatography. This international study evaluated nonadherence in 305 lupus patients with flares using drug levels (HCQ < 200 ng/ml or undetectable desethylchloroquine), and self-administered questionnaires (MASRI < 80%). Drug levels defined 18.4% of the patients as severely nonadherent. In multivariate analyses, younger age, nonuse of steroids, higher body mass index, and unemployment were associated with nonadherence by drug level. Questionnaires classified 23.4% of patients as nonadherent. Correlations between adherence measured by questionnaires, drug level, and physician assessment were moderate. Both methods probably measured two different patterns of nonadherence: self-administered questionnaires mostly captured relatively infrequently missed tablets, while drug levels identified severe nonadherence (i.e., interruption or erratic tablet intake). The frequency with which physicians miss nonadherence, together with underreporting by patients, suggests that therapeutic drug monitoring is useful in this setting. (Trial registration: ClinicalTrials.gov: NCT01509989.).

Are dietary vitamin D, omega-3 fatty acids and folate associated with treatment results in patients with early rheumatoid arthritis? Data from a Swedish population-based prospective study.

BACKGROUND: Dietary intake of vitamin D and omega-3 fatty acids (FA) may be associated with superior response to antirheumatic treatments. In addition, dietary folate intake may be associated with worse response to methotrexate (MTX). The aim of this study was to investigate the association between dietary vitamin D, omega-3 FA, folate and treatment results of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). METHODS: This prospective study was based on data from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, and included 727 patients with early RA from 10 hospitals in Sweden. Data on dietary vitamin D, omega-3 FA and folate intake based on food frequency questionnaires were linked with data on European League Against Rheumatism (EULAR) response after 3 months of DMARD treatment. Associations between vitamin D, omega-3 FA, folate and EULAR response were analysed with logistic regression adjusted for potential confounders. RESULTS: The majority of patients (89.9%) were initially treated with MTX monotherapy and more than half (56.9%) with glucocorticoids. Vitamin D and omega-3 FA were associated with good EULAR response (OR 1.80 (95% CI 1.14 to 2.83) and OR 1.60 (95% CI 1.02 to 2.53), respectively). Folate was not significantly associated with EULAR response (OR 1.20 (95% CI 0.75 to 1.91)). Similar results were seen in a subgroup of patients who were initially treated with MTX monotherapy at baseline. CONCLUSIONS: Higher intake of dietary vitamin D and omega-3 FA during the year preceding DMARD initiation may be associated with better treatment results in patients with early RA. Dietary folate intake was not associated with worse or better response to treatment, especially to MTX. Our results suggest that some nutrients may be associated with enhanced treatment results of DMARDs.

CTLA4-Ig (abatacept) therapy modulates T cell effector functions in autoantibody-positive rheumatoid arthritis patients.

BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease with a strong MHC class II component and where many patients develop characteristic autoantibodies towards the noncoding amino acid citrulline. Such anti-citrullinated protein antibodies (ACPA) have recently been put forward as an independent predictive factor for treatment response by co-stimulation blockade by CTLA4-Ig (abatacept). We have performed a mechanism of action study to dissect T cell functionality in RA patients with long-standing disease undergoing abatacept treatment and the influence of ACPA status. RESULTS: Peripheral blood samples were collected from RA patients as they started CTLA4-Ig treatment and 3 and 6 months later. A general decrease of regulatory T cell subsets was observed in the cohort. Additionally within the ACPA-positive group significant down-regulation of all key T cell effector subsets including Th1, Th2, and Th17 was observed by analyzing cytokines by intracellular flow cytometry and in cell culture supernatants.RA synovial fluid samples were cultured in vitro in the presence or absence of CTLA4-Ig (abatacept). T cell cytokine production was diminished, but without increasing the functional capacity of CD4+CD25hi regulatory T cells as previously demonstrated in the context of TNF-blockade and anti-IL6R therapy. CONCLUSIONS: Our immunological study of T cell functionality in RA patients, both ACPA-positive and ACPA-negative starting biological therapy with the co-stimulation blockade abatacept (CTLA4-Ig) supports the recently published registry study implicating ACPA seropositivity as an independent predictive factor to treatment response as we observed the most striking effect on T cell subset modulation in ACPA-positive patients. These data further support the notion of RA as a disease with several sub-entities, where the ACPA-positive fraction represents a classical HLA-associated autoimmune disorder while ACPA-negative patients may have other driving forces apart from classical adaptive immune responses.

Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol (a novel PEGylated anti-tumor necrosis factor agent) as adjunctive therapy to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with an inadequate response to MTX therapy alone. METHODS: In this 52-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 982 patients were randomized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0, 2, and 4, with a subsequent dosage of 200 mg or 400 mg given every 2 weeks, plus MTX, or placebo plus MTX. Co-primary end points were the response rate at week 24 according to the American College of Rheumatology 20% criteria for improvement (ACR20) and the mean change from baseline in the modified total Sharp score at week 52. RESULTS: At week 24, ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8% and 60.8%, respectively, as compared with 13.6% for the placebo group. Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 (P < 0.001). At week 52, mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg (0.4 Sharp units) or 400 mg (0.2 Sharp units) as compared with that in placebo-treated patients (2.8 Sharp units) (P < 0.001 by rank analysis). Improvements in all ACR core set of disease activity measures, including physical function, were observed by week 1 with both certolizumab pegol dosage regimens. Most adverse events were mild or moderate. CONCLUSION: Treatment with certolizumab pegol 200 or 400 mg plus MTX resulted in a rapid and sustained reduction in RA signs and symptoms, inhibited the progression of structural joint damage, and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX.