Understanding the immunopathophysiology of PsA
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Understanding the mechanism of action by which psoriatic arthritis treatment works and taking a patient’s lifestyle into account can benefit clinicians treating patients with the condition, said Philip J. Mease, MD, of the Swedish Medical Center in Seattle and the University of Washington.
Rheumatoid arthritis is driven by activation of the adaptive immune system, while PsA affects a variety of tissue domains including the synovial lining tissue of joints and inflammation where tendons and ligaments insert into bone.
In that tissue compartment, the immune cells react to micro-trauma to the tendons and ligaments, such as in the Achilles tendon insertion. Significant inflammation and pain can occur in these entheseal insertion sites, which then contributes to the overall pain and disability that patients experience. Virtually every patient with PsA experiences inflammation of the skin and in the spine, notably the lumbar, cervical and sacral iliac areas, Mease said.
Mease explained that the cellular infiltrate of the PsA synovium includes a variety of cells while the rheumatoid synovitis landscape is a bit more uniform T lymphocyte infiltrate.
“Proportionally there is a significant amount of innate immune system activation. The innate immune system is our first line of defense,” he said. “For example, if we're attacked by a virus or bacteria, they adapt to the innate immune system as the first troops that arrived at the scene. And so, they will be certain lymphocytes, but also neutrophils and mast cells and other cells that are primed to respond to an immediate danger.”
Significant differences can be found in the genetic makeup of diseases like lupus, RA ankylosing spondylitis and PsA. However, there are significant overlaps between the genetic footprint of psoriasis and PsA, but there are also some differences with additional genes being commonly present in patients with PsA that may not be present in certain patients with psoriasis, Mease said.
Certain genes like HLA-DR are prominently present in patients with RA during their lifetime, while there are distinct genetic profiles in patients with PsA like HLA-CW6.
“We consider each of these autoimmune diseases to have an important genetic footprint. Now, does this translate into something that is clinically useful? Not very, because we don't measure these genes routinely in commercial laboratories and we aren't yet at a place where we can at birth do a genetic analysis of an individual and predict with high likelihood that they will develop a certain disease at a certain point,” said Mease. “We can say yes, you're more likely than a person who doesn't have this gene to develop this disease, but it has low predictive value. It's not yet ready for primetime to either predict whether a person will develop a particular disease or, as we might see in the future, having therapies which can head the disease off at the pass by manipulating the patient's genetic architecture.”
Commonly used medications have a limited shelf life, meaning the patient may lose benefit from the treatment over time. This window of time may be as short as 6 months until the benefit of the medication wanes in effectiveness. Due to the average benefit of these drugs lasting between 1.5 to 3 years, Mease emphasized the need for several different drugs in a single class like a JAK inhibitor or an interleukin-17 inhibitor.
Concerns about the lack of efficacy of existing treatments are often that the treatment will not work or work adequately to control the patient's inflammation so that clinicians can be assured that the patient can function normally, and the patient can be assured they're not going to have progression of structural damage to their joints. Mease estimated that 40% to 50% of therapies may not get adequate benefit and called for the trial of different therapies.
“Rheumatologists are by and large, a curious bunch and an intellectually interested bunch. They tend to know science and are very interested in immunology,” he said. “So, by definition, most rheumatologists are going to be knowledgeable about and aware of the immunologic pathways by which disease occurs. And in the corollary is knowing the pathways by which the various treatments that we use can benefit that patient’s disease.”
Understanding the mechanism of action by which PsA works is important when selecting a drug that works or replacing a drug that doesn’t. A drug that works in the immunologic pathway of PsA differs from a drug that works in a similar and immunologic pathway of lupus: the TNF cytokine is targeted when treating PsA, but not when treating lupus.
“At a very basic level, it's very important for rheumatologist to understand these pathways, and then as we work through the different treatments for the disease over time, we find we want to know if the patient hasn't had any response to a TNF inhibitor, then we will less likely go to another TNF inhibitor but instead we'll go to an IL-17 or JAK inhibitor or IL-23 inhibitor instead,” Mease said. “So, these kinds of that level of knowledge are important.”
There are multiple classes of medications that are effective and fairly safe, such as TNF inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, JAK inhibitors, IL-23 inhibitors and PDE4 inhibitors, in addition to older oral medications like methotrexate. Using their knowledge of safe and effective medications, Mease suggests clinicians take other factors into account when deciding on a medication such as what disease the patient has, whether the patient shas a preference for oral medication over injected medication and the patient’s insurance coverage.
“The key thing is to enlist the patient in discussion in helping make that choice. It's very important, from my perspective, to make sure the patient has a full understanding of the choices in front of them, both from an efficacy and safety point of view, so that they can participate in that decision, if it's mandated or strongly suggested by the rheumatologist to do this or that and then it backfires, or there's a safety issue or doesn't work, then it doesn't work as well,” Mease said. “You really need the patient to be an equal participant in this treatment choice.”
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