History of Lupus
Early Progress With Lupus Treatment Involves Antimalarials and Corticosteroids
The first medication used for lupus, quinine (an antimalarial), was described by Payne in 1894 (Payne, 1894). Four years later, the use of salicylates in conjunction with quinine was a significant step in lupus therapy (Radcliffe-Crocker, 1898). In the middle of the twentieth century, the treatment of SLE was revolutionized by the discovery of the adrenocorticotrophic hormone and cortisone by Kendall and Hench (Hench, 1952). Corticosteroids and antimalarials are still a major component of lupus therapy. Antimalarials are used primarily for patients with skin and joint involvement, but are also used as background therapy for more severe disease manifestations.
Immunosuppressants Are Introduced into Lupus Treatment
The knowledge of the hyperactive immune systems of lupus patients led to immunosuppressants as a logical next treatment for those with severe disease. The burgeoning field of organ transplantation allowed a shared model for suppressing immune responses and attendant inflammation. One of the earliest agents used was Azathioprine. Cytoxan, an alkylating agent derived in the 1960s from WWI mustard gas, saved lives by preventing mortality from kidney failure and other severe lupus manifestations. This was confirmed in a classic NIH study published in 1986. This trial showed that the combination of Cytoxan and prednisone was superior to prednisone alone in the treatment of lupus nephritis (Austin, et al., 1986). In the late 1990s, CellCept was introduced as an alternative to Cytoxan for the treatment of severe SLE (Ginzler, et al., 2005). Originally developed to prevent transplant rejection, CellCept down-regulates the immune system in a relatively non-specific way (Allison & Eugui, 2000) and was found to improve disease activity in patients with severe SLE with fewer side effects than Cytoxan (Allison & Eugui, 2000).
The early twenty-first century introduced a new class of drugs to the treatment of SLE: the biologics. These medications were created through biological rather than chemically synthesized processes. The first biologic, a drug called Rituximab, targets the B-cells that make antibodies (Pescovitz, 2006). While Rituximab is not specifically directed against B-cells making the lupus-specific antibodies, it is a significant advancement from the global inhibition of the immune system provided by drugs like Cytoxan and CellCept. Rituximab has been used for years in patients with B-cell lymphomas with relatively few side effects (Plosker & Figgitt, 2003).
First Drug Specifically Developed for SLE
In 2011, the Food and Drug Administration approved Benlysta, the first drug that was specifically developed for SLE. This opened the door to even more effective medicines. Benlysta works by suppressing the B-lymphocyte stimulator (BLyS) protein, a key mediator of the immune response. Patients with lupus have elevated levels of BLyS, and it was hoped that inhibiting the protein would quiet the disorder. Phase III clinical trials showed that Benlysta, in combination with standard therapy, significantly reduced the severity of symptoms and lowered several blood biomarkers of the disease compared to standard treatment alone (Navarra, et al., 2011).
Working Towards a Cure
We have come a long way from quinine, but much more still needs to be done. Multiple drugs are being developed to tackle the many facets of lupus. Anti-INF, anti-IL6, anti-IL17/23, anti-CD40, CC-220, anti-CD20, and anti-CD19 are in late phase clinical trials. With each drug that succeeds, we are closer to a cure and to making patients’ lives more normal.