Lack of ‘good disease model’ inhibits treatment decision-making in axial spondyloarthritis
Click Here to Manage Email Alerts
DESTIN, Fla. — Incomplete understanding of axial spondyloarthritis disease process poses challenges for treatment decision making, according to a presenter at the 2023 Congress of Clinical Rheumatology-East.
“Current therapies are not rooted in a thorough understanding of disease pathogenesis,” Joerg Ermann, MD, assistant professor of medicine in the division of rheumatology, immunology & allergy at Brigham and Women’s Hospital and Harvard Medical School.
Biologic treatment of axial spondyloarthritis (axSpA) includes TNF inhibitors, interleukin-17A inhibitors and inhibition of the janus kinase/signal transducer and activator of transcription proteins (JAK/STAT) pathway. But understanding when to use each class remains uncertain, according to Ermann. “There have been no head-to-head trials in this disease,” he said.
It is for this reason that the two main guideline documents — the 2019 American College of Rheumatology/Spondylitis Association of America (SAA)/Spondyloarthritis Research and Treatment Network (SPARTAN) and the 2022 Assessment of Spondyloarthritis International Society (ASAS)/EULAR recommendations — differ.
The two guidelines agree that NSAIDs should be used in the first line. However, EULAR suggests that the second line should be initiated when the patient reaches Ankylosing Spondylitis Disease Activity Score of 2.1, while the ACR recommends changing to a biologic when “symptoms become unacceptably bothersome to the patient and judged by the examining clinician to be due to inflammation,” according to the document.
Ermann explained why the ACR recommendation is a helpful parameter for decision-making. “This ultimately also gives us more flexibility on when to start a patient on ultimately better drugs than nonsteroidals,” he said.
In addition, EULAR does not offer a sequence for TNF, IL-17A or JAK/STAT inhibition, while
the ACR document calls for TNF inhibition first, then IL-17A, then JAK/STAT inhibition with tofacitinib (Xeljanz, Pfizer).
Ermann said the next phase of axSpa research should explore these three drug classes.
Some of that research is underway. For example, he suggested that there is rationale for IL-17A inhibition in these patients. He noted that genome-wide association studies have shown polymorphisms in the IL-23R gene. In addition, the misfolding of HLA-B27 may activate the IL-23/IL-17A axis. Expansion of IL-17-positive producing lymphocytes have also been found in the blood of these patients.
But these data highlight the challenges faced by clinicians and researchers hoping to gain understanding of this disease. “Most of the data we have on the effectiveness of IL-17A are based on IL-23,” Ermann said. “However, IL-23 inhibition did not work.”
Ermann offered a potential explanation for this phenomenon. “It is possible that IL-23 plays a role early in the disease process but does not play a role once the disease is established,” he said. “Maybe it happens in the gut during initiation of disease but is not important during established spinal disease.”
The implication is that by the time a rheumatologist sees a patient with axial spondyloarthritis, it is too late to impact the IL-23 pathway.
Turning to JAK inhibitors, Ermann suggested that there are just as many questions. “Clearly, JAK inhibitors work,” he said. “But we do not understand why. There must be another cytokine or other cytokines that play a role in the JAK/STAT signaling pathway that play a role in the disease process. We just do not know what they are yet.”
But experts are beginning to answer some questions. Ermann reported preliminary data from the SURPASS trial that were presented at ACR last year. “It was the first randomized, controlled trial in axial spondyloarthritis with radiographic progression as the primary endpoint,” he said.
Results showed no difference in this endpoint in patients treated with TNF or IL-17A inhibition. This result is another small piece of the puzzle that may eventually lead to more targeted therapeutic decision-making.
Building from this finding, Ermann laid out some challenges for researchers in the axSpa space to consider. “We do not have a good disease model that explains why patients have symptoms,” he said. “We also do not know how to incorporate data from clinical trials into that disease model.”
Collapse
Ermann J. Ankylosing Spondylitis: How Has Current Understanding of Immunopathogenesis Led to Effective Therapeutic Targets? Presented at: Congress of Clinical Rheumatology-East annual symposium; May 4-7, 2023.
Click Here to Manage Email Alerts