Saturday, March 19, 2011

Lupus Drugs: Anti-malarials/Plaquenil

            Anti-malarials have been used to treat lupus since the 1950’s. In fact, prior to Benlysta’s approval, the last drug approved for lupus was the anti-malarial plaquinel, which was approved in 1956. My understanding, though it may be incorrect, is that lupus patients who were being treated for malaria noticed an improvement of their lupus symptoms. They reported this improvement, it was studied, and plaquinel was approved. (Interesting side note: Viagra came into existence in much the same way. The molecule used in Viagra was originally being investigated for heart symptoms. It was a serendipitous discovery that it also improved…other symptoms, shall we say?)

            For a long time plaquenil was used without anyone really knowing exactly how it worked. However, recently a biological explanation for how plaquenil helps improve lupus was discovered. It would appear that plaquenil blocks some proteins in the “Toll-like Receptor” (or TLR) family. TLRs are proteins that the cell uses as a first line defense against infection. Each TLR is specific for one thing, and only one thing. Some bind to free-floating DNA, others to various bacterial proteins. If they bind to their molecule of choice, they signal to the cell that an infection is occurring, and the immune response is activated.

In an autoimmune disease like lupus, the normal mechanisms that the immune system uses to sense infection get confused. For example, in a healthy person nucleic acids (such as DNA) are never just floating around in the blood; instead they are neatly packaged up in cells. In an infection, on the other hand, DNA from either dead cells or viruses may get dumped into the blood. The immune system has therefore evolved some TLRs to "see" free-floating DNA as a sign that there’s a problem, and to activate an immune response. Unfortunately, in lupus patients there is often free-floating DNA around because the immune system is attacking the body’s own cells, which are then spilling their DNA into the blood. So the immune system is activated as the TLRs see DNA where it shouldn’t be. Plaquenil helps solve this problem by preventing the TLRs from ever seeing the DNA. This helps keep the immune cells from thinking that there’s an infection, and the inflammatory response is therefore kept down.

So is plaquenil an immunosuppressant? I guess that depends on your definition. It does prevent the immune system from “seeing” DNA floating around in the blood. That means even if there is an infection causing the DNA to be there the immune system will not be able to see it. On the other hand, most immunosuppressants work by actually killing off cells in the immune system, which plaquenil does not do. I would personally not put plaquenil in the immunosuppressant class, but as I said before, it depends on what definition you’re using.

Obviously I have to make generalizations to translate immunology findings into English. For further more technical reading, I recommend the following sources:


  1. What I've read is that it was soldiers who were treated for malaria who also had rheumatoid arthritis that brought plaquenil's usefulness to light. (In those days if you were diagnosed with lupus you were basically dead.) That might well have included your great uncle, by the way, who was a ship's captain serving in the Pacific.

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