Editorial

Why all systemic lupus erythematosus patients should be given hydroxychloroquine treatment?

The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer’s disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques. We showed that AQ and analogs have similar effects although having a higher cytotoxicity. Herein, two new series of compounds were synthesized by replacing 7-chloroquinolin-4-amine moiety of AQ by 2-aminomethylaniline and 2-aminomethylphenyle moieties. Their structure activity relationship was based on their ability to modulate APP metabolism, Aβ release, and their cytotoxicity similarly to CQ. Two compounds 15a, 16a showed interesting and potent effect on the redirection of APP metabolism toward a decrease of Aβ peptide release (in the same range compared to AQ), and a 3–10-fold increased stability of APP carboxy terminal fragments (CTFα and AICD) without obvious cellular toxicity at 100 µM.

Hydroxychloroquine has unique immunomodulatory properties and an attractive adverse effect profile. Over the past 10 years, research has led to significant updates in clinical recommendations concerning the optimal use of hydroxychloroquine and monitoring of patients taking it. We discuss updated recommendations concerning hydroxychloroquine daily dosing, retinopathy screening, serologic monitoring, use in smokers, use in pregnant women, and adverse effect risk and monitoring. This review can hopefully serve as an aid to dermatologists and help ensure they continue using hydroxychloroquine safely and effectively.

Hydroxychloroquine (HCQ) is a widely used medication for the treatment of rheumatoid arthritis and systemic lupus erythematosus. An increasing body of evidence supports actions of this drug that are not directly related to its immunosuppressive or anti-rheumatic properties. The objective of this systematic review is to characterize the spectrum of conditions that might be responsive to treatment with HCQ.

PubMed was searched using the MeSH for HCQ with relevant subheadings and the limits of human topics and English language. Four-hundred and fifty-six abstracts from this search were examined individually to exclude those that were not focused on the objectives of this review. The resulting 76 articles were grouped according to topic areas and reviewed in detail.

HCQ has been reported to have therapeutic effects in a wide array of conditions, including diabetes mellitus, dyslipidemias, coagulopathies, infectious diseases and malignancies. Mechanisms of action responsible for these effects likely include altered signaling through cellular receptors, post-glycosylation modifications of infectious agents, changes in levels of inflammatory mediators and inhibition of autophagy. Many of the pathways are likely dependent on drug-induced changes in intra-endosomal acidity.

The use of, and interest in, HCQ has spread into many areas of medicine. Actions of this drug may be directly beneficial to patients with non-rheumatic conditions such as diabetes mellitus or viral infections. Further understanding of underlying mechanisms has potential to reveal modifiable pathogenic pathways that might elucidate approaches to the design of more effective therapeutics for many chronic diseases.

La prevalencia de anticuerpos antifosfolípidos (aFL) en la población general es del 1%. No todos los pacientes asintomáticos con aFL tienen el mismo riesgo de desarrollar trombosis, por lo que la profilaxis rutinaria con ácido acetilsalicílico (AAS) no está justificada en términos de beneficio-riesgo.

En base a la evidencia actual, la prevención primaria solo estaría indicada en los grupos de alto riesgo, incluyendo: a) pacientes con anticuerpos anticardiolipina (aCL) persistentemente elevados a títulos altos, anticoagulante lúpico (AL) repetidamente positivo, o con positividad de los aCL, AL y de los anticuerpos anti-β2 glucoproteína I (triple positividad) con independencia de su título; b) en situaciones de alto riesgo trombótico por presencia concomitante de otros factores de riesgo para trombosis (hipertensión arterial, inmovilización, cirugía, etc.); c) en presencia de una enfermedad autoinmune sistémica, particularmente el lupus eritematoso sistémico (LES), y d) durante el embarazo.

El tratamiento profiláctico en estos pacientes se basa en el empleo de AAS. En situaciones concretas también son útiles la heparina de bajo peso molecular y la hidroxicloroquina.

The prevalence of antiphospholipid antibodies (aPL) in the general population is 1%. Not all asymptomatic patients with aPL antibodies have the same risk for thrombosis, and consequently routine prophylaxis with acetylsalicylic acid (ASA) is not justified in terms of risk-benefit in all asymptomatic carriers. Based on current evidence, primary prevention is indicated only in high-risk groups including the following: a) in patients with anticardiolipin antibodies (aCL) at persistently high titers, repeatedly positive lupus anticoagulant (LA) or aCL positivity, LA and anti-beta2 glycoprotein I (triple positivity) regardless of titer; b) in situations of high thrombotic risk due to the concomitant presence of other thrombotic risk factors (hypertension, immobilization, surgery, etc.); c) in the presence of a systemic autoimmune disease, particularly systemic lupus erythematosus, and d) during pregnancy. Prophylactic treatment in these patients is based on the use of ASA. In specific situations, low-molecular-weight heparin and hydroxychloroquine are also useful.

Obstacles facing therapeutic trials in systemic lupus erythematosus (SLE) include the low incidence, seriousness, complexity, and clinical polymorphism of the disease. A large-scale multicenter design has been required in most cases. Over the last few years, several biologics have been evaluated as treatments for lupus nephritis or for the skin and joint manifestations of SLE. The central role for the B-cell in SLE, together with improved knowledge of the targets on the B-cell surface, has prompted efforts to develop monoclonal antibodies as treatments for SLE. The two available monoclonal antibodies are rituximab (anti-CD20 antibody) and belimumab (anti-BlyS antibody). The results obtained with belimumab were used to develop a new measurement tool, the SLE Responder Index (SRI), and prompted an application for a license to use belimumab in SLE. Other targets identified on the B-cell surface are being evaluated.

Les arthrites au cours du lupus érythémateux systémique (LES) sont épisodiques et bien limitées chez la plupart des patients. Cependant, dans certains cas, des arthralgies/arthrites réfractaires peuvent apparaître et être mal contrôlées par les AINS et d’autres traitements. Les atteintes articulaires mais aussi des autres organes doivent être prises en compte avant l’instauration d’un autre traitement. Dans le contexte de nouvelles biothérapies très efficaces, nous avons revu et analysé toutes les données publiées dans Medline sur le traitement des arthrites lupiques, ainsi que les recommandations françaises (PNDS et CRI). Chez les patients lupiques qui présentent des symptômes articulaires isolés et intermittents, les AINS en cures courtes peuvent être utilisés en première intention. Si les symptômes articulaires sont plus sévères ou récurrents, de faibles doses de corticoïdes (≤ 10 mg/j) associées à un traitement antimalarique sont recommandées. Les infiltrations de corticoïdes peuvent être éventuellement utiles, en cas d’arthrites persistantes localisées. Si les symptômes articulaires persistent, les indications thérapeutiques dépendent des autres organes affectés. Dans les formes articulaires pures résistantes au traitement ou corticodépendantes, qui nécessitent une dose inacceptable de prednisone chez un patient dont la compliance au traitement est confirmée, le méthotrexate en association à un antimalarique est à proposer en première intention. En cas d’échec au traitement ou d’intolérance, le mycophénolate mofétil ou même l’azathioprine représente une alternative thérapeutique. En dernier recours, après avoir apprécié le rapport bénéfice–risque individuel, le léflunomide, le belimumab, le rituximab voire l’abatacept peuvent être discutés au cas par cas. Les anticorps anti-TNF ne peuvent être envisagés que dans des circonstances exceptionnelles.