Bispecific antibodies tethering innate receptors induce human tolerant-dendritic cells and regulatory T cells

There is an urgent need for alternative therapies targeting human dendritic cells (DCs) that could reverse inflammatory syndromes in many autoimmune and inflammatory diseases and organ transplantations. Here, we describe a bispecific antibody (bsAb) strategy tethering two pathogen-recognition receptors at the surface of human DCs. This cross-linking switches DCs into a tolerant profile able to induce regulatory T-cell differentiation. The bsAbs, not parental Abs, induced interleukin 10 and transforming growth factor β1 secretion in monocyte-derived DCs and human peripheral blood mononuclear cells. In addition, they induced interleukin 10 secretion by synovial fluid cells in rheumatoid arthritis and gout patients. This concept of bsAb-induced tethering of surface pathogen-recognition receptors switching cell properties opens a new therapeutic avenue for controlling inflammation and restoring immune tolerance

Features and Outcomes of Microcrystalline Arthritis Treated by Biologics: A Retrospective Study

International audienceOBJECTIVES: The usual treatments for crystal-associated arthritis are sometimes contraindicated; thus, new therapies against interleukin-1beta (IL-1) have been developed. We evaluated the characteristics of patients who received biological treatment for crystal-associated arthritis. PATIENTS AND METHODS: We conducted a multicentric retrospective observational study in six rheumatology units in western France. Patients receiving a biological treatment for crystal-associated arthritis between 1 January 2010 and 31 December 2018 were included. Improvement was defined as at least a 50% decrease in the count of synovitis and C-reactive protein level. RESULTS: Forty-six patients were included: 31 (67.4%) were treated for gouty arthritis, and 15 (32.6%) for calcium pyrophosphate crystal deposition disease (CCPD). The first biotherapy used was anakinra for 14 patients (93.3%) with CCPD and 31 patients (100.0%) with gout. The first biotherapy course was more efficient in treating gout than in treating CCPD, with success in 28 patients (90.3%) and 5 patients (35.7%), respectively (p = 0.001). Six patients (42.9%) with CCPD stopped their first biotherapy course because of side effects. Among the patients with gout, urate-lowering therapy was more frequently used after (100%) than before the first biotherapy course (67.7%) (p = 0.002). CONCLUSION: Anakinra was prescribed for cases of refractory crystal-associated arthritis or cases with contraindications for usual treatments. The efficacy of anakinra in treating CCPD was not obvious. Patients with CCPD had more side effects. The biotherapy was introduced with a long-term objective, while anti-IL-1 therapies are approved for acute crises only

Therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal disease: A systematic literature review informing EULAR points to consider

The objectives of this review were to collect and summarise evidence on therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases and to inform the EULAR Task Force for the formulation of evidence-based points to consider. A systematic literature review (SLR) was performed, covering technical aspects and (clinical) utility of TDM, to answer 13 research questions. MEDLINE, Embase and Cochrane were searched until July 2020. American College of Rheumatology and EULAR abstracts were also considered for inclusion. Data were extracted in evidence tables and risk of bias assessment was performed. For the search on technical aspects, 678 records were identified, of which 22 papers were selected. For the clinical utility search, 3846 records were identified, of which 108 papers were included. Patient-related factors associated with biopharmaceutical blood concentrations included body weight, methotrexate comedication and disease activity. The identification of a target range was hampered by study variability, mainly disease activity measures and study type. Evidence was inconsistent for multiple clinical situations in which TDM is currently applied. However, for some particular scenarios, including prediction of future treatment response, non-response to treatment, tapering and hypersensitivity reactions, robust evidence was found. There is currently no evidence for routine use of proactive TDM, in part because published cost-effectiveness analyses do not incorporate the current landscape of biopharmaceutical costs and usage. This SLR yields evidence in favour of TDM of biopharmaceuticals in some clinical scenarios, but evidence is insufficient to support implementation of routine use of TDM

Publisher Correction: Rheumatological features of Whipple disease

International audienc

Rheumatological features of Whipple disease

International audienceWhipple disease (WD) is a rare infectious systemic disease. Rheumatologists are at the frontline of WD diagnosis due to the early rheumatological manifestations. An early diagnosis is crucial, as usual anti-rheumatic drugs, especially TNF inhibitors, may worsen the disease course. We conducted a retrospective multicentre national study from January 2010 to April 2020 to better characterize the rheumatological features of WD. Classic WD (CWD) was defined by positive periodic acid-Schiff (PAS) staining of a small-bowel biopsy sample, and non-CWD (NCWD) was defined by negative PAS staining of a small-bowel biopsy sample but at least one positive Tropheryma whipplei (TW) polymerase chain reaction (PCR) for a digestive or extradigestive specimen. Sixty-eight patients were enrolled, including 11 CWD patients. Twenty patients (30%) received TNF inhibitors during the WD course, with inefficacy or symptom worsening. More digestive symptoms and systemic biological features were observed in CWD patients than in NCWD patients, but both patient groups had similar outcomes, especially concerning the response to antibiotics and relapse rate. Stool and saliva TW PCR sensitivity were both 100% for CWD and 75% for NCWD and 89% and 60% for small-bowel biopsy sample PCR, respectively. WD encountered in rheumatology units has many presentations, which might result from different pathophysiologies that are dependent on host immunity. Given the heterogeneous presentations and the presence of chronic carriage, multiple TW PCR tests on samples from specific rheumatological sites when possible should be performed, but samples from nonspecific digestive and extradigestive sites also have great value

EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases

OBJECTIVE: To develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs). METHODS: The points-to-consider were developed in accordance with EULAR standardised operation procedures by a multidisciplinary task force from eight European countries, based on a systematic literature review and expert consensus. Level of evidence and strength of the points-to-consider were determined, and mean levels of agreement among the task force were calculated using a 10-point rating scale. RESULTS: Six overarching principles and 13 points-to-consider were formulated. The level of agreement among the task force for the overarching principles and points-to-consider ranged from 8.4 to 9.9.The overarching principles define TDM and its subtypes, and reinforce the underlying pharmacokinetic/pharmacodynamic principles, which are relevant to all biopharmaceutical classes. The points-to-consider highlight the clinical utility of the measurement and interpretation of biopharmaceutical blood concentrations and antidrug antibodies in specific clinical scenarios, including factors that influence these parameters. In general, proactive use of TDM is not recommended but reactive TDM could be considered in certain clinical situations. An important factor limiting wider adoption of TDM is the lack of both high quality trials addressing effectiveness and safety of TDM and robust economic evaluation in patients with RMDs. Future research should focus on providing this evidence, as well as on further understanding of pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals. CONCLUSION: These points-to-consider are evidence-based and consensus-based statements for the use of TDM of biopharmaceuticals in inflammatory RMDs, addressing the clinical utility of TDM

EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases

Objective To develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs). Methods The points-to-consider were developed in accordance with EULAR standardised operation procedures by a multidisciplinary task force from eight European countries, based on a systematic literature review and expert consensus. Level of evidence and strength of the points-to-consider were determined, and mean levels of agreement among the task force were calculated using a 10-point rating scale. Results Six overarching principles and 13 points-to-consider were formulated. The level of agreement among the task force for the overarching principles and points-to-consider ranged from 8.4 to 9.9.The overarching principles define TDM and its subtypes, and reinforce the underlying pharmacokinetic/pharmacodynamic principles, which are relevant to all biopharmaceutical classes. The points-to-consider highlight the clinical utility of the measurement and interpretation of biopharmaceutical blood concentrations and antidrug antibodies in specific clinical scenarios, including factors that influence these parameters. In general, proactive use of TDM is not recommended but reactive TDM could be considered in certain clinical situations. An important factor limiting wider adoption of TDM is the lack of both high quality trials addressing effectiveness and safety of TDM and robust economic evaluation in patients with RMDs. Future research should focus on providing this evidence, as well as on further understanding of pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals. Conclusion These points-to-consider are evidence-based and consensus-based statements for the use of TDM of biopharmaceuticals in inflammatory RMDs, addressing the clinical utility of TDM