RA Beginnings: Before the Painful Joints

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Recent years have seen a paradigm shift in the conceptualization of rheumatoid arthritis (RA), with the focus moving away from understanding and managing established disease and toward elucidating the local and systemic processes that occur during the preclinical phase -- usually among individuals who carry genetic predispositions to the disease and/or have detrimental environmental exposures.

It's now recognized that in the majority of patients who ultimately develop RA, the initiating events of loss of immune self-tolerance begin long before the appearance of a swollen, tender joint.

A prominent aspect of pre-RA is the appearance of circulating autoantibodies, primarily rheumatoid factor (RF) and, in particular, antibodies to citrullinated protein antigens (ACPA), although there are various others, such as antibodies to carbamylated and acetylated proteins. Additional biomarkers that have been detected in the pre-RA period include survivin and phenotypic changes in B and T cell subsets, as well as inflammatory markers such as cytokines and chemokines.

"Picture a small amount of immune inflammation and dysregulation that then expands as from a candle to a campfire to a forest fire," explained Kevin D. Deane, MD, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, who has written extensively on the early phase and pathogenesis of RA.

As he recently wrote in Arthritis & Rheumatology, "Based on current data, it appears that this early stage of RA is characterized by early reactivity with a limited number of self-antigens, and limited systemic inflammation that is followed by evolution over time of expanding innate and adaptive responses and tissue injury until some threshold is crossed and clinically apparent inflammatory arthritis/RA develops."

However, the key factors and pathways that trigger a loss of tolerance and autoimmunity and then drive the transition to clinical disease largely remain uncertain. But it appears likely that there is a complex interplay between genetic susceptibility factors, environmental exposures, and systemic and local pathogenic events such as citrullination at mucosal sites.

What Genetic Influences are Involved in Rheumatoid Arthritis?

It's long been apparent that genetic factors are involved in RA because of the increased prevalence within families. It has been estimated that at least 40% of risk can be ascribed to genetic influences, with the strongest effects for seropositive RA seen among first-degree relatives. Moreover, the prevalence is notably high among certain ethnic groups such as Native Americans.

Researchers have also identified many specific genetic loci that contribute to RA risk. "The strongest of the genetic risk factors is a set of alleles within the Major Histocompatibility Complex that encode amino acid sequences that predict structural similarities in the Human Leukocyte Antigen (HLA) peptide-binding groove and are termed in aggregate the shared epitope," Deane and colleagues wrote in Best Practice & Research: Clinical Rheumatology.

Many of these alleles reside in the HLA DRB1 region. The shared epitope has also been implicated in the progression from pre-RA to clinical disease. In one study that followed 100 ACPA-positive patients who had nonspecific musculoskeletal complaints, the presence of the shared epitope was associated with a twofold increase of progression to inflammatory arthritis.

Are There Environmental Factors in Rheumatoid Arthritis?

Numerous lifestyle and environmental factors have been linked with an increased risk of RA, the strongest of which is exposure to tobacco, which has been estimated as being responsible for up to 30% of the environmental risk. Smoking is believed to result in increased citrullination of proteins -- conversion of the amino acid arginine to citrulline -- which the immune system then perceives as non-self and results in an immune response in the form of ACPA antibodies. This process can begin in the lung with long-term direct exposure to smoke in the pulmonary mucosal tissue.

In addition, in a study that included almost 1,000 first-degree relatives of RA patients, joint inflammation was associated with cigarette smoking even among those who were negative for RA autoantibodies, suggesting that smoking itself may have early negative systemic effects in the joints.

Moreover, a report presented at the 2021 European League Against Rheumatism virtual congress found that even passive smoking in childhood was associated with an increased risk for RA in adulthood, particularly among those who were ACPA positive and carried the shared epitope alleles.

In that study, which followed almost 100,000 healthy French women since 1990, the hazard ratio for the subsequent development of RA among those who reported exposure to passive smoking in childhood was significantly elevated, at 1.24 (95% CI 1.01-1.51). Furthermore, women who themselves smoked and had been exposed to passive smoking developed RA earlier than nonsmokers who had no passive smoke exposure, at age 66.5 years compared with 60.6.

Occupational exposures also have been implicated in RA, such as exposures to silica, asbestos, and coal dusts. Studies also have shown risks with exposure to high levels of particulate air pollution.

Dietary factors also appear to play a role, with elevated risks being observed for low intake of vitamin D and antioxidants and also with high intake of red meat, sugar, and sodium. Many studies also have found decreased risks with fish and omega-3 fatty acid consumption.

Therefore, said Deane, individuals at risk for RA, such as those who have first-degree relatives with the disease, should follow a healthy diet, "which probably means adopting a diet that's akin to the Mediterranean diet -- high in fruits, vegetables, and whole grains but low in animal products."

Role of Microbes and Mucosa in Rheumatoid Arthritis

There have long been suspicions that pathogens may be responsible, in conjunction with other factors such as genetic predisposition and smoke exposure, for triggering the loss of immune tolerance and the subsequent development of RA. While the initial studies of mucosal inflammation and antibody formation focused on the surface of the lung, other mucosal tissues also appear to contribute.

"At some point in preclinical RA, at a mucosal surface (e.g., the oral cavity, lung, gut) interactions between microbes, potentially other environmental factors (e.g., tobacco smoke) and host factors lead to mucosal inflammation and initial breaks in RA-related immune tolerance," Deane wrote.

As he also explained to MedPage Today: "During the pre-RA phase, we think mucosal events are critically important. During that nonarticular phase of disease, we think is when the mucosal properties drive the initial break in tolerance, and in certain individuals the result is not only mucosal inflammation but also systemic inflammation that spreads into the joints."

In the periodontal mucosa, studies have suggested that Porphyromonas gingivalis, a common bacterium in periodontal disease, may act as a trigger for loss of tolerance through production of peptidylarginine deiminase, an enzyme involved in citrullination.

Antibodies to the citrullinated antigens have been detected in individuals with periodontal disease who have not yet developed joint symptoms. In addition, other pathogens involved in periodontal disease such as Anaeroglobus and Prevotella have been detected in pre-RA patients, while elevations in serum ACPA and severe periodontitis have been observed in first-degree RA relatives.

The gut microbiome is increasingly being considered another mucosal site where RA could be triggered. Fecal samples in pre-RA have suggested that there are changes in bacterial diversity, and Prevotella species have been identified in these samples. Along with the increase in Prevotella copri, reductions have been observed in Bacteroides and other beneficial bacteria in fecal samples of patients with new-onset RA.

It also is increasingly being understood that mucosal processes are involved in the transition from pre-RA to clinical disease, and may play a role in disease development once systemic autoimmunity has occurred.

Can Rheumatoid Arthritis be Stopped/Reversed?

With the greatly increased understanding of the events and processes involved in pre-RA, researchers have begun to consider interventions during the nonarticular phase of disease, asking whether RA can be stopped or reversed before articular damage occurs.

A study that randomized 83 patients with arthralgia and who were positive for either ACPA or RF to injections of dexamethasone 100 mg at baseline and 6 weeks found no benefit for the steroid, with arthritis developing in about 20% of both groups during 26 weeks of follow-up. Another trial, known as STAPRA, found no benefit for atorvastatin in high-risk individuals and was stopped prematurely.

Some other initial data, however, have been promising. In the PRAIRI study, published in Dec. 2018, a total of 81 patients who were positive for both ACPA and RF but who had no clinically apparent arthritis were randomized to receive a single infusion (1,000 mg) of rituximab (Rituxan) or placebo and followed up for a mean 29 months. By that time point, the rate of arthritis development did not differ significantly between the active treatment group and the placebo group (34% vs 40%), but the development of symptomatic arthritis in one-quarter of the patients was delayed by 12 months in the rituximab group.

And most recently, a multicenter study known as ARIAA randomized 98 patients who were ACPA positive and had MRI signs of inflammation (synovitis, tenosynovitis, or osteitis) to receive subcutaneous abatacept (Orencia), 125 mg weekly, or placebo for 6 months and then no further treatment for 12 months.

The preliminary results, presented as a plenary abstract at the American College of Rheumatology virtual annual meeting in Nov. 2021, indicated that 61% of patients given abatacept showed improvement on at least one of the MRI signs, compared with only 31% of patients receiving placebo (P=0.0043). In addition, clinical arthritis developed in 34.7% of patients in the placebo group compared with only 8.2% in the abatacept group.

In his presentation, the lead investigator, Jürgen Rech, MD, of University Clinic Erlangen in Germany, said that additional 18-month data should indicate "whether the effect of a time-limited intervention with abatacept has a sustained effect on the inhibition of progression to RA."

And while the 18-month data were not available in time for inclusion in his abstract, he said, "I did see the results yesterday and these were also significant at 18 months. This means that 6 months of treatment with abatacept can delay or even prohibit the development of RA after 18 months."

The study results were "very exciting," according to Deane, who was not involved in the study. "I think it's going to move the field ahead."

Other studies are underway, such as StopRA in the U.S., with Deane as the lead investigator, which is randomizing patients with high levels of ACPA to hydroxychloroquine or placebo for a year, and APPIPRA in Europe, in which patients with high ACPA and arthralgia receive a year of subcutaneous abatacept or placebo.

"We'll have to wait for those, but it's exciting to start thinking about prevention," Deane said. "I can't tell people to go out right now and find out what their risk for RA is and get going on prevention. But I think we're getting close."