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Axial spondyloarthritis (axSpA) is the currently favored term for a spectrum of painful disorders affecting the spine, and most specifically the sacroiliac joints. Its prototypical form was ankylosing spondylitis, defined some 40 years ago as a condition characterized by the presence of radiographic sacroiliitis. However, ankylosing spondylitis today is considered a misnomer because while it implies the presence of inflammation, x-rays only show actual damage, a late-stage manifestation of disease, and not the inflammation characteristic of early disease.

It's now well recognized that the disease begins long before radiographic evidence can be detected, with inflammation being visible on MRI years before damage is present. That disease state, which in some, but not all, patients progresses to full-blown ankylosing spondylitis, has been referred to as nonradiographic axSpA, but experience in recent years has demonstrated that the pain, disease burden, and response to therapy is similar among patients with nonradiographic and radiographic axSpA. Accordingly, the Assessment in SpondyloArthritis International Society now advises that in clinical practice the umbrella term axial spondyloarthritis be used to refer to the entire range of disease.

Patterns of Disease

The typical presenting symptom is back pain that persists for more than 3 months. The axial disease -- characterized by inflammatory pain in the lower back and buttocks that is worse during the second half of the night and early morning, and which improves with exercise and worsens with rest -- is accompanied in many patients by peripheral arthritis (usually of the lower limbs) as well as extra-articular manifestations such as psoriasis, inflammatory bowel disease (IBD), and anterior uveitis. The inflammatory pain often is relieved by the use of nonsteroidal anti-inflammatory drugs.

The disease typically is insidious in onset, beginning during the third decade of life, with a male predominance approaching 3:1. The overall prevalence has been estimated to be 0.1% to 1.4%, but this is highly dependent on the background prevalence of the HLA-B27 genetic locus within the major histocompatibility complex class I region. The HLA-B27 gene variants are present in peripheral blood in 70% to 90% of affected patients.

The connection between HLA-B27 and axSpA was first reported 50 years ago, and the highest rates of HLA-B27 have been observed in northern Europe, while the lowest rates have been reported in southern Africa and Japan. In recent years, other genetic loci have also been implicated, including ERAP1 and the interleukin (IL)-23 receptor.

Because axSpA typically develops during young adulthood, the impact on social, educational, occupational, and economic life can be considerable, with many patients having difficulties with work, especially among those with longer disease duration and who have physically demanding jobs.

As the disease advances, with the development of bone changes including edema, osteitis, and remodeling, the final outcome in the past typically involved widespread spinal fusion with its attendant severe disability.

Pathogenesis

Recent work has been unraveling some of the clues to the early events and mechanisms that ultimately lead to clinical disease, with a general consensus being that the disease pathogenesis involves an interplay between genetic and environmental factors such as mechanical stress and leakage of pathogens into the bloodstream from the gut microbiome.

The primary site of disease initiation is at the enthesis, which is the site at which the ligament anchors to bone. The enthesis is a load-bearing structure with a specific immune microenvironment that is susceptible to various triggers. One such trigger is biomechanical stress, which can involve tension and compression and changes to the subchondral bone. "Biopsies from the Achilles tendon and spine have shown that in a genetically primed host, entheseal trauma can initiate the early stages of axial spondyloarthritis," said Atul Deodhar, MD, a professor of medicine and medical director of rheumatology at the Oregon Health & Science University in Portland.

"The enthesis is the key pathological target in axSpA, just as the synovial lining is the target in rheumatoid arthritis and the skin is the target in psoriatic arthritis," explained Dennis McGonagle, MD, PhD, a professor of investigative rheumatology at the University of Leeds in England. "This is a site of high physical stress and microdamage, and these points of ligament anchorage into bone triggers widespread underlying bone inflammation, which causes a lot of the pain these patients experience."

Infection also has been postulated as playing a triggering role. "There's been a long history implicating particular types of infections in the pathogenesis of axial spondyloarthritis," said Liron Caplan, MD, PhD, associate professor at the University of Colorado in Aurora. Recent research has suggested that sources of infections can include skin damage in patients with psoriasis and the intestinal mucosa for patients with IBD manifestations.

Intestinal dysbiosis has been an area of intense interest in the development of axSpA, with 10% of patients having clinical IBD and up to 70% of patients showing at least subclinical inflammation of the gut. Research into end-stage ankylosing spondylitis has shown that the normal tight junctions between the epithelial cells of the intestine are loosened, resulting in a permeable "leaky gut" that allows pathogens and microbial antigens to enter the bloodstream, ultimately reaching the enthesis where an immune reaction is triggered. The resulting enthesitis leads to secretion of proinflammatory cytokines and upregulation of inflammatory pathways such as the IL-23/17 axis.

"We have confirmed that patients with axial spondyloarthritis have gut microdysbiosis, with several different abnormal gut microbes having been identified," explained Deodhar in an interview. "But we don't know if this is an epiphenomenon or causative. In other words, do the abnormal gut microbes come first and then you develop axial disease or does having HLA-B27 change your gut microbiome?"

Biopsies, MRI studies, and animal models have also demonstrated that the first detectable bone change is the development of subchondral bone marrow edema, followed by the development of granulation tissue that can erode the bone and/or result in new bone formation.

The Spinal Immune System

"It's very difficult to study the early phases of axial spondyloarthritis compared to psoriasis, where it's easy to get skin tissue, or colitis where you can do biopsies, or even rheumatoid arthritis where arthroscopy can readily procure tissue from the joint," said McGonagle.

"Because the earliest abnormalities in AS [ankylosing spondylitis] occur deep in the body, within the bone and the spine, the tissue is very inaccessible," he told 番茄社区.

To elucidate these early events, he and his team have been working with a large group of spinal orthopedic surgeons, obtaining spinal specimens from non-axSpA patients undergoing surgery for conditions such as scoliosis, comparing them with specimens from patients with chronic axSpA requiring surgery for complications such as fractures. Accordingly, they have been characterizing the normal spinal immune system to explore what might go wrong in the early phases of axSpA.

"Specifically, what we then do is take tissue from normal subjects and treat it as if it had been exposed to an infectious trigger, from a leaky gut for example, and then activate the spinal cellular immune cells to determine what might happen in the early phase of disease," McGonagle said.

"And for patients with chronic disease who are undergoing reparative surgery, we can undertake single cell sequencing to try to characterize clonotypic T cells," he said. These expanded T-cell clones may be reacting to some self or foreign proteins, so the goal is to identify putative antigens that could drive disease.

Implications for Treatment

"The therapies for axSpA have come from nothing 25 years ago to well-established biologic classes today including the tumor necrosis factor and interleukin-17 blockers and Janus kinase inhibitors. So we've become pretty good at treating the disease, but only up to 50% of people have very good responses, so we're very interested in a better understanding of early disease because we know that when you treat early, patients do better," McGonagle said.

Further explorations include using MRI to more clearly visualize the early spinal events, expanding the knowledge on the role of the gut and specific pathogens in triggering disease, and identifying potential autoantigens that could be driving the disease through molecular mimicry.

"So there's great interest in manipulating all these factors with the goal of early intervention, prevention, and even a cure, based on the identification of rogue clones that drive the HLA-B27-associated inflammation," McGonagle concluded.

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