Advances in rheumatoid arthritis pathogenesis ‘nothing short of extraordinary’
Researchers’ understanding of the pathogenesis of rheumatoid arthritis has grown considerably in recent years, laying the groundwork that may inform a new generation of therapeutic targets and therapies.
“Ultimately, one can envision using the understanding of the natural history, biology, endotypes and stages of RA to identify interventions in an individual who is in the at-risk stage,” Kevin D. Deane, MD, PhD, William P. Arend endowed chair for rheumatology research at the University of Colorado Anschutz Medical Campus, and director of the University of Colorado Autoimmune Disease Prevention Center, told Healio. “We may then improve symptoms that they have in that stage, as well as prevent them from getting worse and developing ‘full-blown RA,’ which can also be termed ‘clinical RA.’”
Research has targeted everything from antibodies to clinical factors. Genetic and genomic research has kept pace.
“Advances made in the genomics of RA since the early 2000s have been nothing short of extraordinary, with a large number of genetic variations now known to contribute to disease susceptibility,” Ted R. Mikuls, MD, MSPH, of the Veterans Affairs Nebraska-Western Iowa Health Care System, and the University of Nebraska Medical Center, told Healio.
Two key data sets published in recent years have set the stage not only for increasing investigation into RA pathogenesis, but also for the therapeutic targets that may ultimately result.
‘Conspire to promote disease progression’
In a 2022 paper published in Immunity, Alivernini and colleagues painted a broad picture of the current understanding of RA pathogenesis. They discussed the multiyear prodromal phase of systemic immune dysregulation, a process that may begin in the mucosal surfaces, giving way to clinical symptoms. Inflammatory processes and immune reactivity, primarily in the synovium, can lead to pain and articular damage, according to the findings.
A similar paper was published in 2021 by Meuller and colleagues in Cells. There, the authors described the importance of autoantibodies in diagnosis, prognosis and treatment decision-making.
“Epigenetic alterations, post-translational modifications, glycosylation, autophagy, and T-cells” are all involved in RA pathogenesis, according to the findings. The researchers added that exploring how these factors connect and impact each other “would contribute to a deeper insight” into all aspects of RA including its causes, mechanisms, progression and treatment.
“The articles by Drs. Alivernini and colleagues, and Mueller and colleagues, nicely outline the observed broad immune abnormalities that are present in both systemic circulation in RA, as well as within the synovium,” Deane said. “They also mention that some of these processes, including autoantibody abnormalities and some cellular abnormalities, occur prior to the appearance of clinically apparent inflammatory arthritis, or ‘clinical RA,’ which is classically defined as a swollen joint consistent with synovitis on physical examination.”
For Mikuls, that deeper investigation of antibodies will be critical to understanding RA moving forward.
“There is no doubt that the evolving story of citrullination and anti-citrullinated protein antibody (ACPA) production in RA has provided a critical window into RA pathogenesis,” he said. “In addition to being an important diagnostic tool, we increasingly understand that ACPA and other disease-related autoantibodies are likely more than just diagnostic or prognostic biomarkers, with increasing evidence pointing to the fact that these autoantibodies conspire to promote disease progression in RA.”
Meanwhile, Kaleb Michaud, MD, of the University of Nebraska Medical Center, stated he was “surprised to see,” in the above papers, biologics like TNF inhibitors described as new or future treatments, “when we have 25 years of experience with them.”
“It is a shame to not have more on the conventional synthetic DMARDs, as well as what we know about how they impact the signaling pathways and help reduce inflammation and RA activity,” he said.
“I would also include triple therapy, another older treatment that’s listed as new, possibly among the new strategies,” Michaud added.
That said, the deeper understanding of RA pathogenesis described in these two papers may allow for both newer and older strategies to be used during the all-important preclinical phase of the disease.
Preclinical stage ‘most exciting’
“Although we still need to understand clinical RA better to improve therapies, in my opinion the most exciting aspect of RA is the preclinical/pre-RA/at-risk stage,” Deane told Healio.
In a 2018 paper published in Nature Reviews Rheumatology, Holers and colleagues set out to examine the various mucosal processes that may influence the development of systemic immunity and autoimmunity. According to the authors, patients who are at high risk for future RA demonstrate evidence of chronic systemic and mucosal inflammation. Thus, these pre-clinical processes could be targets for prevention strategies.
“In serologically positive individuals without arthritis, designated as ACPA positive at-risk, the presence of mucosal inflammatory processes associated with the presence of local ACPA production has been demonstrated,” Holers and colleagues wrote.
Holers and many of the same researchers built on this work in a 2024 study, also in Nature Reviews Rheumatology.
“Recent work now suggests the presence of multiple distinct mucosal site-specific mechanisms that drive RA evolution,” they wrote. “Indicatively, subsets of individuals at-risk of RA and patients with RA harbor a fecal bacterial strain that has exhibited arthritogenic activity in animal models and that favors T helper 17 (TH17) cell responses in patients.”
Periodontal inflammation and oral microbiota may also be implicated through breaches in the mucosal barrier, according to Holers and colleagues.
“Herein, we argue that mucosal sites and their associated microbial strains can contribute to RA evolution via distinct pathogenic mechanisms, which can be considered causal mucosal endotypes,” they wrote.
According to Deane, emerging research suggests that each stage of RA — from “normal” to first detectable autoimmunity, then to systemic/circulating autoimmunity and joint disease — occurs because of failed checkpoints in the control of autoimmunity.
“Furthermore, there may be mucosal processes and even microbial factors that drive the development of RA,” he said.
Advances in genetics and other factors are keeping pace with the excitement surrounding the emerging data on preclinical RA and mucosal involvement.
“Although the shared epitope hypothesis was published almost 40 years ago, we now have a much greater understanding of how the shared epitope contributes to disease development, and particularly how this genetic background biases us toward anti-citrullinated protein responses,” Mikuls said.
The more recent advances may aid in the identification of mechanisms at the cellular level and more broadly, according to Mikuls.
“These mechanisms will likely link to environmental exposures to disease risk and progression,” he said.
According to Mikuls, the most important goal is to use this information to develop therapeutic targets.
“I anticipate this being a major focus in the field moving forward, paralleling the rapid advancements being made in genomic assessments and the bioinformatics tools that are so central to these efforts,” he said.
However, genetics are just part of the picture that has been described in recent literature.
Exploring novel RA strategies
“It is increasingly clear that investigations focused on a single post-translational modification (PTM) or a single autoantibody are likely to have limited relevance to RA, where diseased tissues simultaneously harbor multiple PTMs in close proximity and where autoantibodies, such as ACPA and rheumatoid factor, have been shown to play a synergistic role in promoting inflammation,” Deane said.
In his lab, Mikuls has focused largely on a specific PTM, malondialdehyde-acetaldehyde (MAA), a protein adduct that is produced during oxidative stress.
“Our studies and those from other groups clearly show that MAA — and possibly other PTMs — act an important second or even third hit in RA development,” he said.
For example, a protein harboring both citrulline and MAA activates macrophages in a manner that is unique from a protein that has only one of these PTMs, according to Mikuls.
“In turn, these cells communicate with tissue fibroblasts, creating a highly aggressive cell phenotype that is both pro-inflammatory and pro-fibrotic,” he said. “Directly targeting these PTMs or the signaling pathways that are engaged could represent a novel strategy in management.”
Beyond PTMs, Mikuls highlighted other efforts to translate the understanding of RA pathogenesis into therapeutic targets.
“A growing body of literature suggests that glycosylation and cell autophagy could provide other novel targets,” he said. “Data demonstrating that glycosylation of antibody — including disease specific ACPA — are altered in RA in a way that amplifies the pathogenicity.”
Similarly, cell autophagy may also play a “central role” in disease pathogenesis, according to Mikuls.
“Specifically in the sustained generation of citrullinated peptides leading to tolerance loss and autoimmune responses that are unique to RA,” he said.
Prevent patients from ‘getting worse’
“The future of RA will need to focus on understanding how to identify what stage of RA development individuals may be in, as well as what specific biology is present at that stage and in that individual, so it that can be targeted to both treat the current condition as well as prevent progression to a next worst stage,” Deane said. “Importantly, we are also learning that although the diagnosis of RA is applied to many people, there are many subtypes/endotypes.”
Identifying those subtypes and endotypes can help clinicians find the right treatment pathway. However, more data on this topic are necessary to develop targeted and newer treatments.
According to Deane, delineating seropositivity vs. seronegativity is an important way to differentiate RA endotypes that may have different potential therapeutic targets.
“However, there are also differences based on age and sex, as well as synovial pathology and other immunologic features,” he said. “As such, we will need to understand these endotypes across all the stages of RA, and how to use testing or other factors to identify them.”
References:
Alivernini S, et al. Immunity. 2022;doi:10.1016/j.immuni.2022.11.009.
Holers MV, et al. Nat Rev Rheumatol. 2018;doi:10.1038/s41584-018-0070-0.
Holers MF, et al. Nat Rev Rheumatol. 2024;doi:10.1038/s41584-024-01154-0.
Meuller AL, et al. Cells. 2021;doi:10.3390/cells10113017.
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