Chloroquine (CQ) and its hydroxylated analog, hydroxychloroquine (HCQ), are 4-aminoquinoline initially used as an antimalarial treatment. CQ and HCQ (4-aminoquinoline, 4-AQ) are today used in ...rheumatology, especially to treat rheumatoid arthritis and systemic lupus erythematosus. Their mechanism of action revolves around a singular triptych: 4-AQ acts as alkalizing agents, ionized amphiphilic molecules, and by binding to numerous targets. 4-AQ have so pleiotropic and original mechanisms of action, providing them an effect at the heart of the regulation of several physiological functions. However, this broad spectrum of action is also at the origin of various and original side effects, notably a remarkable chronic systemic toxicity. We describe here the 4-AQ-induced lesions on the eye, the heart, muscle, the nerves, the inner ear, and the kidney. We also describe their prevalence, their pathophysiological mechanisms, their risk factors, their potential severity, and the means to detect them early. Most of these side effects are reversible if treatment is stopped promptly. This 4-AQ-induced toxicity must be known to prescribing physicians, to closely monitor its appearance and stop treatment in time if necessary.
JAK inhibitors are recent treatments. Many publications have appeared in recent years, exposing treatment efficiencies in phases 2 and 3 studies, or their tolerance profile in various rheumatological ...diseases. We propose here a systematic review of JAK inhibitors, from their mechanism of physiological action up to the estimation of their current risk benefit balance, and their possible future applications.
In order to better synthesize the data, we organized this review into 10 essential points.
1- What is the role of JAK/Stat pathway?
2- How can a single signaling pathway regulate as many different signals?
3- What are the commercialized JAK inhibitors and their validated indications in humans today?
4- What is the level of efficiency of JAK inhibitors in inflammatory diseases?
5- What is the delay of efficiency of JAK inhibitors?
6- Where is the place of JAK inhibitors in the therapeutic strategy today?
7- What is the infectious tolerance profile of JAK inhibitors?
8- What is the non-infectious safety profile of JAK inhibitors?
9- What is the cost of JAK inhibitors compared to other DMARDs?
10- What future prospects for JAK inhibitors?
•JAK inhibitors modulate a central communication node for cells•Commercialized JAK inhibitors are superior to methotrexate in rheumatoid arthritis•Safety profile of JAK inhibitors is reassuring, but long-term effects are unknown•JAK inhibitors are actually tested in >150 registered clinical trials
Objective
Immunoglobulin G4-related disease (IgG4-RD) is a rare orphan disease. Lung, pleura, pericardium, mediastinum, aorta and lymph node involvement has been reported with variable frequency and ...mostly in Asian studies. The objective of this study was to describe thoracic involvement assessed by high-resolution thoracic computed tomography (CT) in Caucasian patients with IgG4-RD.
Methods
Thoracic CT scans before treatment were retrospectively collected through the French case registry of IgG4-RD and a single tertiary referral centre. CT scans were reviewed by two experts in thoracic imagery blinded from clinical data.
Results
48 IgG4-RD patients with thoracic involvement were analysed. All had American College of Rheumatology/European League Against Rheumatism classification scores ≥20 and comprehensive diagnostic criteria for IgG4-RD. CT scan findings showed heterogeneous lesions. Seven patterns were observed: peribronchovascular involvement (56%), lymph node enlargement (31%), nodular disease (25%), interstitial disease (25%), ground-glass opacities (10%), pleural disease (8%) and retromediastinal fibrosis (4%). In 37% of cases two or more patterns were associated. Asthma was significantly associated with peribronchovascular involvement (p=0.04). Among eight patients evaluated by CT scan before and after treatments, only two patients with interstitial disease displayed no improvement.
Conclusion
Thoracic involvement of IgG4-RD is heterogeneous and likely underestimated. The main thoracic CT scan patterns are peribronchovascular thickening and thoracic lymph nodes.
Pulmonary involvement of IgG4‐associated disease is a rare condition with no codified treatment apart from steroid administration. We report here the case of a patient with pulmonary involvement of ...IgG4‐RD successfully managed with Rituximab, in induction and maintenance therapy. This original case could support the use of Rituximab in rare situations of steroid‐resistant or steroid‐dependent pulmonary IgG4‐RD.
We report here the case of a patient with pulmonary involvement of IgG4‐RD successfully managed with Rituximab, in induction and maintenance therapy. This original case could support the use of Rituximab in rare situations of steroid‐resistant or steroid‐dependent pulmonary IgG4‐RD.
IL-1β is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1β-mediated disease such as systemic juvenile ...idiopathic arthritis (sJIA). Leukocyte microvesicles (MVs) may be a mechanism of IL-1β secretion. The first objective of our study was to characterize IL-1β-positive MVs obtained from macrophage cell culture supernatants and to investigate their biological functions
and
. The second objective was to detect circulating IL-1β-positive MVs in JIA patients.
MVs were purified by serial centrifugations from PBMCs, or THP-1 differentiated into macrophages, then stimulated with LPS ± ATP. MV content was analyzed for the presence of IL-1β, NLRP3 inflammasome, caspase-1, P2X7 receptor, and tissue factor (TF) using ELISA, Western blot, or flow cytometry. MV biological properties were studied
by measuring VCAM-1, ICAM-1, and E-selectin expression after HUVEC co-culture and factor-Xa generation test was realized.
, MVs' ability to recruit leukocytes in a murine model of peritonitis was evaluated. Plasmatic IL-1β-positive MVs were studied
in 10 active JIA patients using flow cytometry.
THP-1-derived macrophages stimulated with LPS and ATP released MVs, which contained NLRP3, caspase-1, and the 33-kDa precursor and 17-kDa mature forms of IL-1β and bioactive TF. IL-1β-positive MVs expressed P2X7 receptor and released soluble IL-1β in response to ATP stimulation
. In mice, MVs induced a leukocyte peritoneal infiltrate, which was reduced by treatment with the IL-1 receptor antagonist. Finally, IL-1β-positive MVs were detectable in plasma from 10 active JIA patients.
MVs shed from activated macrophages contain IL-1β, NLRP3 inflammasome components, and TF, and constitute thrombo-inflammatory vectors that can be detected in the plasma from active JIA patients.
Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy. The current pathophysiologic paradigm suggests that the ADAMTS13 deficiency leads to Ultra Large-Von Willebrand ...Factor multimers accumulation with generation of disseminated microthrombi. Nevertheless, the role of endothelial cells in this pathology remains an issue. In this review, we discuss the various clinical, in vitro and in vivo experimental data that support the important role of the endothelium in this pathology, suggesting that ADAMTS13 deficiency may be a necessary but not sufficient condition to induce TTP. The "second hit" model suggests that in TTP, in addition to ADAMTS13 deficiency, endogenous or exogenous factors induce endothelial activation affecting mainly microvascular cells. This leads to Weibel-Palade bodies degranulation, resulting in UL-VWF accumulation in microcirculation. This endothelial activation seems to be worsened by various amplification loops, such as the complement system, nucleosomes and free heme.
Ocular immunotherapy-related adverse events (IRAEs), although rare, can be sight-threatening. Our objective was to analyze ocular IRAEs diagnosed in France from the marketing of immune checkpoint ...inhibitors (ICPIs) until June 2021 and to review the literature. We collected the cases of 28 patients (36 ocular IRAEs), occurring after an average of 17 weeks (±19). Forty-six percent of patients were treated for metastatic melanoma. Anti-PD1 agents were responsible for 57% of the IRAEs. Anterior uveitis was the most common (44%), followed by panuveitis (28%). Of 25 uveitis cases, 80% were bilateral and 60% were granulomatous. We found one case with complete Vogt-Koyanagi–Harada syndrome and one case of birdshot retinochoroidopathy. The other IRAEs were eight ocular surface disorders, one optic neuropathy, and one inflammatory orbitopathy. Seventy percent of the IRAEs were grade 3 according to the common terminology of AEs. ICPIs were discontinued in 60% of patients and 50% received local corticosteroids alone. The literature review included 230 uveitis cases, of which 7% were granulomatous. The distributions of ICPIs, cancer, and type of uveitis were similar to our cohort. Ocular IRAEs appeared to be easily controlled by local or systemic corticosteroids and did not require routine discontinuation of ICPIs. Further work is still warranted to define the optimal management of ocular IRAEs.
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