Multifaceted effects of hydroxychloroquine in human disease,☆☆,

https://doi.org/10.1016/j.semarthrit.2013.01.001Get rights and content

Abstract

Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

Introduction

Drugs derived from cinchona bark have been used for centuries to treat maladies including malaria [1]. In the twentieth century, the widespread use of quinacrine by the US military as malaria prophylaxis was accompanied by other observations suggesting efficacy for rheumatologic conditions [2]. During the 1950s, the hydroxychloroquine (HCQ) derivative of quinacrine showed a more favorable usage profile with less eye toxicity than chloroquine itself and the use of this agent for treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) became common. In RA, HCQ is usually a component of medication combinations, including triple-drug therapy with methotrexate and sulfasalazine, a regimen that has been advocated as a safe, well-tolerated alternative to more expensive biologic therapies [3], [4]. Efficacy in SLE has long been recognized, especially for skin manifestations [5], [6], [7] but other components of this disease including serositis, arthritis and hematologic abnormalities also are improved by treatment with HCQ [8]. While the use of HCQ in renal SLE has not been advocated as primary treatment, recent evidence suggests that use of HCQ can retard renal damage [9] and patients who have been treated with HCQ have significantly lower rates of developing end-stage renal disease [10]. Even patients with membranous lupus nephritis show benefits of HCQ [11]. Furthermore, the use of HCQ in SLE patients is associated with improved overall survival [12], decreased accrual of damage [13], [14] and lower rates of infection [15]. Other data suggest that onset of SLE may be delayed if HCQ is given in preclinical stages [16]. Discontinuation of HCQ is associated with an increased risk of flares in SLE disease activity [17], [18]. HCQ is safe to use during pregnancy and cross-sectional analyses suggest that it can reduce the risk of fetal cardiac abnormalities in mothers with SSA/SSB autoantibodies [19], [20]. Increased recognition that cardiovascular disease is a cause of premature morbidity and mortality in RA and SLE has also led to interest in HCQ, which has a beneficial cardiovascular profile [21].

These recent insights have led to renewed interest in this old drug, with some suggesting that all patients with SLE, including children, should be treated with HCQ, regardless of disease manifestations [1], [22], [23], [24].

Other observations have expanded the scope of diseases or conditions that might be favorably impacted by treatment with HCQ beyond rheumatologic diseases. This in itself is not an entirely new observation, and a previous review of this subject noted several conditions, including hyperlipidemia, for which the strength of evidence for beneficial effects of chloroquine or HCQ was quite strong [25]. While some areas of potential applicability might be thought of as predictable, such as in infectious diseases, given that the original application of chloroquine itself was for malaria, others are not so obvious. Furthermore, past observations, some of them decades old, regarding actions of HCQ that correlated with lower risks of blood clots and improvement in lipid abnormalities have taken on increasing relevance with the recognition that RA and SLE are associated with elevated risks of cardiovascular events and that anti-phospholipid antibodies are responsible for most of the thrombotic events in SLE. Several recent reports have highlighted beneficial effects in patients with hyperglycemia or frank diabetes mellitus, a new area of potential therapy. Given the heightened interest and new information, a review of the pleomorphic effects of HCQ and the wider implications for disease management is timely.

Section snippets

Methods

The initial MeSH search of PubMed was for hydroxycholoroquine, including all subheadings except “economics” and “history”. Search results were restricted to “human” and English language. This initial search produced more than 1,300 results. A second more focused search was then done with the hydroxychloroquine MeSH but excluding the additional subheadings: “chemistry”, “chemical synthesis”, “isolation and purification”, “urine”, and the two previous exclusions. The search results were

Results

HCQ is labeled for use in the treatment of RA and lupus in both discoid and systemic forms. It is also often used for treatment of associated rheumatic conditions such as Sjögren Syndrome. Evidence supporting the efficacy of HCQ in RA has been summarized in a systematic review [26] and has been shown in randomized controlled clinical trials (RCTs), some of which are listed in Table 1 [27], [28], [29]. Although it is efficacious as a single agent, HCQ has in the past decade had a more widespread

Discussion

Treatment of autoimmune diseases with HCQ and related antimalarials has been commonplace for over half a century. Many long-term studies have now documented improved outcome in terms of organ damage and overall survival in patients who have received these medications. Examination of the list of benefits associated with HCQ is striking and strongly endorses the idea recently articulated by a leading lupus investigator that the indication for use of HCQ in SLE is the diagnosis itself. Over the

Conclusion

HCQ has long-term benefits in SLE and RA, and has become a standard component of therapy for patients with these diseases. Other data suggest that HCQ and related antimalarials may have more wide-reaching medical indications in conditions including diabetes mellitus, infectious diseases, coagulopathies and malignancies. Further studies of mechanisms of action and targets of these drugs are likely to provide insights that would permit development of even more effective treatments for many

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      Hydroxychloroquine (HCQ) is one of the oldest drugs used in rheumatology and has been proposed over time as a therapeutic agent in a wide range of pathologies, including infectious diseases, immune disorders, diabetes, dyslipidemia, and neoplasia [1].

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    M.S. was supported by a grant from the Research and Education Foundation of the American College of Rheumatology.

    ☆☆

    N.J.O. was supported in part by a CURE grant from the State of Pennsylvania Department of Health.

    N.J.O and D.R.K. were supported by NIH/NIAMS P50 AR055503.

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