Spondyloarthritis - Episode 11
John D. Reveille, MD, and Philip J. Mease, MD, highlight the newer mechanisms of action in ankylosing spondylitis and psoriatic arthritis.
John D. Reveille, MD: Secukinumab inhibits or blocks IL-17, interleukin-17, which is a cytokine that is very important in the TH17 pathway—that includes activating TNF (tumor necrosis factor), as well as a variety of other cytokines which have been shown to be elevated in the blood of AS (ankylosing spondylitis) patients. And in doing so, by decreasing the inflammation, it also does a great deal to lessen subjective disease activity, functional impairment, and radiographic progression.
Philip J. Mease, MD: There are three medications that do not have an anti-TNF mechanism of action that have been approved for the treatment of psoriatic arthritis. These include ustekinumab, apremilast, and secukinumab.
Ustekinumab is a drug which inhibits the cytokines IL-12 and IL-23. And many think that the predominant mechanism is through its inhibition of IL-23. This affects the TH17 cell pathway since IL-12, IL-23 are important cytokines in the differentiation and stimulation of TH17 cells, which produce interleukin-17. IL-23 has shown to be very effective in treating skin psoriasis. And in the Summit I and Summit II trials, it was shown to be effective in treating arthritis, enthesitis, dactylitis, as well as affecting all the other domains of psoriatic arthritis that are important. So, this medication is efficacious. It is relatively safe. It’s given once every 3 months after an induction phase, so it’s fairly convenient for patients.
Apremilast is a phosphodiesterase-4 (PDE4) inhibitor which works by reducing intracellular signaling in potentially inflammatory immunologic cells. PDE4 inhibition leads to an increase of cyclic ANP (atrial natriuretic peptide) in the cell, which then leads to a reduction in the production of proinflammatory cytokines by those immune cells. This is believed to be the mechanism of action of the drug in treating the disease. It has been shown to be efficacious in treating the arthritis component, as well as enthesitis, dactylitis, and skin disease. It’s an oral medication, unlike the large proteins which are biologic medications which have to be injected. It’s taken twice a day, 30 mg.
Its issues have been initial tolerability, problems with nausea, vomiting, diarrhea—in some instances—as well as headache. We often can find that patients, if they take it in a low dose, initially can manage to get through this in the first phase of using it, and then ultimately, oftentimes, those side effects go away. And then the patient can tolerate the medicine just fine and continue using it. Long-term use has shown the drug to be very safe. There’s virtually no signal in terms of infection, or malignancy, or cardiovascular problems, and there is no laboratory monitoring that is required. So, it’s been very interesting as a medication to use, particularly earlier in the treatment ladder—say, after methotrexate and before a biologic medication.
The most recently approved medication is an interleukin-17A inhibitor known as secukinumab. Secukinumab has shown significant efficacy in the treatment of arthritis, enthesitis, and dactylitis. It’s been able to demonstrate highly effective treatment of the skin disease and nail disease. There is evidence of inhibition of radiographic progression, and it is also useful for domains such as fatigue, quality of life, and function. So, it does all the things that we would like for a medicine in psoriatic arthritis to do. It is relatively safe. There is, of course, a warning for serious infection. It’s serious with any of the biologic medications. There’s been a handful of cases of modest candidiasis, primarily in the mouth or skin. And there have been occasional cases of neutropenia, but not serious. From a safety perspective, we consider this to be a relatively safe drug and a very good addition to our armamentarium for treating psoriatic arthritis.