Systemic lupus erythematosus – long considered to be an orphan disease – is now center stage and has been recognized as a major unmet need within the field of rheumatology. The Cover Story of this issue of Healio Rheumatology provides a broad overview of an exciting moment in drug development through the eyes of some of the key opinion leaders in the field.
In 2011, we witnessed the approval of belimumab, the first biologic agent for systemic lupus erythematosus (SLE), which was a meaningful addition to our armamentarium. However, the palate of therapies remains far underdeveloped in comparison to rheumatoid arthritis, psoriatic arthritis and the spondyloarthropathies. According to our SLE consultants, much of the reason for this lagging state is our failure to understand the complex biology of SLE. Industry has improved our situation through a growing number of clinical trials in the field. Also yielding significant impact are a number of influential organizations dedicated to scientific investigation such as the Lupus Research Institute, The Alliance for Lupus Research and the Lupus Foundation of America.
Leonard H. Calabrese
Among the reasons for optimism in biologic drug development for SLE are early signs that targeting the long-studied interferon pathway may be yielding positive results. It is well known that SLE is often characterized by the presence of what has been labeled as “displaying an IFN signature.” This refers to an increased expression of type 1 IFN-regulated genes, hence the IFN signature, and has been reported in blood and tissue cells from patients with SLE and other autoimmune diseases.
While overexpression of IFN-related genes may be identified in more than 50% of SLE patients, lingering doubts have remained as to whether this is cause or effect. Furthermore, an IFN signature is complex and has varying genetic phenotypes. It is hardly specific for SLE and can be seen in numerous autoimmune disorders, such as Sjögren’s syndrome and SLE, as well as immunodeficiency diseases, such as Aicardi–Goutières spectrum disorders and HIV infection.
Early attempts to target this pathway were disappointing but, as noted by Richard Alan Furie, MD, and others, newer agents appear to be yielding promising results in phase 2 trials with phase 3 underway. Perhaps we are at the beginning of a new pipeline of agents that may not only be effective in SLE, but also have immune-mediated inflammatory disease-like qualities and be useful in related autoimmune and inflammatory diseases. Also of note are new agents that target B-cell signaling, activation and survival, which may further strengthen the armamentarium.
Tinge of Caution
It is all sounding so good — so why the tinge of caution? I am a firm believer in the pan-Asiatic notion of “yin and yang” and I think most scientists are as well. We see, in virtually all new drugs developed, a duality of increasing efficacy with some form of untoward toxicity. In fact, we should expect this duality as in the notion of yin and yang they are actually complementary. The trick is in the balance, of course.
My main concerns focus on the potential impact of targeting type 1 IFN, which is an integral component of the integrated immune response with particular importance in the area of antiviral immunity. In animal models, type 1 IFN is critical in controlling viral replication and T-cell anti-viral responses. Suppression of type 1 IFN results in more severe forms of numerous acute viral infections including influenza, West Nile and others.
Its role in the control of chronic and latent viral infections is less well understood. In humans, deficiency of type 1 IFN is most frequently secondary to defects in downstream signaling, such as STAT1, TYK2 UNC-93B and other molecules. Patients with such defects are clearly at increased risk for serious and fatal opportunistic infections. Even in the early trials of anti-IFN agents discussed in the Cover Story, an increased rate of herpes zoster has already been seen in some. As Gregg J. Silverman, MD, said “the more you use IFN [therapy], the more herpes zoster you get.” This should be an adverse event of special interest and studied carefully.