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The Nine Lives of Hydroxychloroquine
11 May 2015
Hydroxychloroquine is one of many medications frequently used in rheumatology practice. Its remarkable versatility is attested by its routine use in lupus, in patients with an autoimmune coagulopathy, in patients with rheumatoid arthritis, as well as those with a low-level inflammatory arthropathy. It’s an amazing medication, with a novel history and wide array of indication and multiple actions that we now better understand. The HCQ story begins in 1638 when the wife of the Viceroy of Peru, Countess Cinchona, acquired malaria while living in the New World. Rather than getting the “approved” therapy, blood-letting, she was treated by an Incan herbalist with the bark of a tree (eventually, named for the countess-Cinchona Tree). Her response was dramatic; when the Viceroy returned to Spain, he brought with him large supplies of the powder for general use, which at the time was controlled by the Church and was thus called “Jesuit’s Powder”.
It took nearly two centuries for the active substance, Quinine, to be isolated from the bark (and was eventually to make a name for itself as a tonic to be added to gin). Over the next century, quinine would become a common component in folk medicines and patent remedies for the treatment of malaria in the southern states of America, as well as for generic malaise. By the 1940s, quinine, or rather its derivative chloroquine, was recognized for its anti-malarial properties and found use among troops fighting in the Pacific during WW-II. However, it was noted that this compound had significant toxicities. In 1945, a modification of this compound via hydroxylation led to the development of HCQ, which was found to be less toxic and remains in use, without change, to this day. Over time, physicians began to experiment with the medication and, in the early 1950s, began to use it for the treatment of SLE. After the success in that disease (at least success relative to the other available agents which were basically none), it was tried in another arthropathy, RA. However, in the quest to get better responses, physicians would “push” the dose and, not surprisingly, toxicities, most notable retinal toxicity, began to present itself as a limiting feature of the medication. Not deterred, physicians adjusted the dose and began to consider using it in combination therapy, which became popular in the 1980s and has culminated in the recent studies showing the notable efficacy of triple therapy when HCQ was combined with MTX and sulfasalazine.
Most of the science regarding HCQ’s mechanism of action falls in the realm of speculation. There is evidence that one of its primary effects is on the lysosome, where it accumulates. Once there, it can stabilize the lysosomal membrane and elevate the intra-organelle pH, leading to inactive acid proteases, decreased receptor recycling, inhibition of protein/cytokine production and secretion, and interference with intracellular inflammatory pathways such as ERK and MAP kinase. Recently, there is some evidence that it also inhibits certain segments of “innate immunity” (that basic immunity which links us to jellyfish), specifically the toll-like receptors. Through its action on TLR3/4, synovial fibroblasts are less likely to become activated. Its effect on TLR7/9 inhibits TNF production.
I’m a clinician, not a molecular biologist, and what I want to know is: does it work and where or when? The most impressive work has come from the lupus literature. This underappreciated medication has been clearly shown to reduce the number of SLE flares, reduce the severity of SLE flares when they occur, can in some cases lead to “remission” including lupus nephritis, increase the risk of flares when stopped, and decrease the doses of prednisone needed to control the disease. In at least one study, the use of HCQ increased survival in patients with SLE by 70%. Of equal importance, HCQ has been shown to decrease the risk of thrombosis in patients who are anti-phospholipid antibody positive. Although no studies have been done to specifically look at it during pregnancy, most feel it is safe to continue through pregnancy in patients with SLE, despite its long T1/2 of 40 hours and its ability to cross the placenta with ease. In a study of 133 pregnancies in patients on HCQ there were no differences in fetal outcome compared to 70 pregnancies seen in a control group. One has to weigh the potential unknown risks of HCQ against the known risk of pregnancy outcome in SLE patients who flare.
http://rheumnow.com/blog/nine-lives-hydroxychloroquine
It would seem so…
Noice!